Diagnostic Pathology - Hospital Autopsy PDF

FYFE

MILLER

Billie Fyfe, MD Professor of Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey

Dylan V. Miller, MD Clinical Associate Professor of Pathology University of Utah School of Medicine Director of Electron Microscopy and Immunostains Intermountain Central Laboratory Salt Lake City, Utah

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1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

DIAGNOSTIC PATHOLOGY: HOSPITAL AUTOPSY

ISBN: 978-0-323-37676-1

Copyright © 2016 by Elsevier. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/ permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this ﬁeld are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identiﬁed, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Publisher Cataloging-in-Publication Data Diagnostic pathology. Hospital autopsy / [edited by] Billie Fyfe and Dylan V. Miller. pages ; cm Hospital autopsy Includes bibliographical references and index. ISBN 978-0-323-37676-1 (hardback) 1. Autopsy--Handbooks, manuals, etc. 2. Autopsy--Methods--Handbooks, manuals, etc. I. Fyfe, Billie. II. Miller, Dylan V. III. Title: Hospital autopsy. [DNLM: 1. Autopsy--methods--Atlases. QZ 35] RB57 .I434 2015 616.07/59--dc23 International Standard Book Number: 978-0-323-37676-1 Cover Designer: Tom M. Olson, BA Printed in Canada by Friesens, Altona, Manitoba, Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

Dedications To the giants who patiently mentored me at Mayo Clinic (Drs. Edwards, Parisi,

Baldwin basement and later Stabile 9. To Drs. Collins and Sinard and many colleagues on the CAP Autopsy Resource Committee for opening my eyes to a wider world of pathology practice. To the many able minds who helped conceive, gestate, and deliver the book’s content and whose names dignify its pages. To Dave, Angie, and Kellie at Amirsys/Elsevier for their patience and trust. And most of all to Tonya, for her undying tolerance and support.

DVM

This book is dedicated with gratitude to my mentors, who gave me the courage

and opportunity to pursue autopsy pathology, and to my mentorees, who make the work so rewarding. This project would not have been possible without the forward vision of the Amirsys/Elsevier team, especially Angela Terry, who supported this unique addition to their pathology collection, and the tremendous expertise shared by Dylan Miller and all of the authors. As always, I must thank my sons, Justin and Alexander, who make everything worthwhile, and my parents, who encouraged me from the beginning.

Contributing Authors Brandon T. Larsen, MD, PhD

Leslie A. Litzky, MD

Assistant Professor of Pathology Department of Pathology Banner – University Medical Center University of Arizona College of Medicine Tucson, Arizona

Professor, Department of Pathology and Laboratory Medicine Perelman School of Medicine University of Pennsylvania Chief, Section of Medical Pathology, Hospital of the University of Pennsylvania Subspecialty Director, Thoracic Pathology, Section of Surgical Pathology Philadelphia, Pennsylvania

Monica P. Revelo, MD, PhD Professor of Pathology Department of Pathology University of Utah School of Medicine Salt Lake City, Utah

Rebecca A. Irvine, MD, FRCPA Glebe, NSW, Australia

George P. Batsides, MD Assistant Professor of Surgery Chief, Section of Cardiac Surgery Surgical Director, Mechanical Circulatory Support Division of Cardiac Surgery Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey

Anatomic and Clinical Pathology Resident Department of Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey

Christine Minerowicz, MD Resident of Pathology Department of Laboratory Medicine and Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey

Harold Sanchez, MD, FCAP Associate Chief of Pathology Department of Pathology Hospital of Central Connecticut New Britain, Connecticut

Roy H. Rhodes, MD, PhD Professor Director, Neuropathology Medical Director, RWJUH EM Services Department of Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey

Paisit Paueksakon, MD Associate Professor Associate Director Division of Renal Pathology/Electron Microscopy

! Department of Pathology, Microbiology, and Immunology Vanderbilt University Medical Center Nashville, Tennessee

Hasini Reddy, MD, DPhil Department of Pathology, Dalhousie University Director of Neuropathology The Moncton Hospital Moncton, New Brunswick, Canada

Rachel Hudacko, MD Medical Director, Department of Pathology/Laboratory St. Anthony Community Hospital Warwick, New York Clinical Instructor, Department of Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey

Patrick Lento, MD Professor of Clinical Pathology and Medicine New York Medical College Valhalla, New York

Corinne L. Fligner, MD Professor, Department of Pathology Adjunct Professor, Department of Laboratory Medicine Director, Autopsy and After Death Services, UW Pathology University of Washington Seattle, Washington

Vidhya Nair, MBBS, MD, FRCPC Associate Professor Department of Pathology and Molecular Medicine McMaster University Cardiovascular Pathologist, Hamilton Health Sciences Hamilton, Ontario, Canada

Elizabeth H. Hammond, MD Professor of Pathology and Adjunct Professor of Medicine (Cardiology) University of Utah School of Medicine Pathology Consultant Intermountain Healthcare Salt Lake City, Utah

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Preface Declining rates of hospital autopsies have not diminished the enthusiasm of those of us who

" #$% & % ' * ' " ! # Engaging young pathologists in autopsy is vital to preserving what is arguably the bedrock of all pathology knowledge. This volume aims to present the hospital autopsy as it is really practiced — with real case presentations, approaches to dissection, chart review focusing, and reporting % #$ +% && trainees and new pathologists, as well as those who unfortunately don’t get the chance to perform autopsies routinely. The format follows other volumes related to surgical pathology in the Diagnostic Pathology # " " % ' % ! *% % sense as a way to emphasize the role that autopsy plays in modern medicine. Making diagnoses

% % processes in surgical pathology. One key distinction between autopsy and surgical pathology is the number of stakeholders

* % -" ' 0

% #1 % ' ! 2% autopsies, impact families and communities through the answers that the autopsy can provide, and help pathologists enjoy the diagnostic journey.

Billie Fyfe, MD Professor of Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey

Acknowledgments Text Editors Dave L. Chance, MA, ELS Arthur G. Gelsinger, MA Nina I. Bennett, BA Sarah J. Connor, BA Tricia L. Cannon, BA $# Lisa A. Gervais, BS

Image Editors 33# 4 Lisa A. M. Steadman, BS

Medical Editor Michael B. Ward, MD

Illustrations Lane R. Bennion, MS Laura C. Sesto, MA Richard Coombs, MS

Art Direction and Design Tom M. Olson, BA Laura C. Sesto, MA

Lead Editor Angela M.G. Terry, BA

Production Coordinators Angela M.G. Terry, BA Rebecca L. Hutchinson, BA

xii

Sections PART I - Autopsy Fundamentals 56$178-1 % 56$179-% 56$17:-% 6

PART II - Organ System Approach to Autopsy 56$178-% ;' 56$179-

xiii

Endocrine System

PART I

I-2-54

Billie Fyfe, MD

Central Nervous System

Autopsy Fundamentals

I-2-60

Hasini Reddy, MD, DPhil

Peripheral Nervous System

SECTION 1 Introduction

I-2-66

Roy H. Rhodes, MD, PhD

Integumentary System

I-2-70

Dylan V. Miller, MD

History of Autopsy

I-1-2

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Autopsy Safety

Oral Cavity

I-2-74

Billie Fyfe, MD

I-1-6

Billie Fyfe, MD

Medical Devices

I-2-78

Brandon T. Larsen, MD, PhD

Laboratory Testing SECTION 2 Autopsy Performance

Chemistry

I-2-82

Rachel Hudacko, MD

Microbiology

External Examination Medical Intervention

I-2-8 I-2-12

Billie Fyfe, MD

Postmortem Radiography and Virtual Autopsy I-2-16

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Cardiovascular System

I-2-20

Dylan V. Miller, MD

Respiratory System

I-2-88

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Postmortem Imaging

Internal Examination Body Cavities

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Cytology

Brandon T. Larsen, MD, PhD

Postmortem Changes and External Examination

I-2-84

SECTION 3 Autopsy Consent and Reporting

I-2-24

Autopsy Consent

Leslie A. Litzky, MD

Hematopoietic System

I-2-28

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Gastrointestinal System

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

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I-3-100

Dylan V. Miller, MD

Death Certificate

I-3-102

Billie Fyfe, MD

I-2-42

Rachel Hudacko, MD & Jeanine Chiaffarano, DO

Genitourinary System

Consent Process and Legal Considerations

Autopsy Reporting I-2-34

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Hepatobiliary System

I-2-94

Billie Fyfe, MD

I-2-48

Autopsy Report

I-3-106

Corinne L. Fligner, MD & Dylan V. Miller, MD

Presenting Autopsy Findings Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

I-3-108

Genitourinary

PART II

Pregnancy Complications

Organ System Approach to Autopsy

II-1-74

Acute Renal Failure Monica P. Revelo, MD, PhD & Paisit Paueksakon, MD

SECTION 1 Sudden and Unexpected Death

Endocrine Adrenal Insufficiency

II-1-4

CNS Seizure Disorders

II-1-92

Hasini Reddy, MD, DPhil

Vidhya Nair, MBBS, MD, FRCPC & Dylan V. Miller, MD

II-1-8

Cardiomyopathy

II-1-88

Patrick Lento, MD

II-1-2

Billie Fyfe, MD

Acute Myocardial Infarction

II-1-84

Dylan V. Miller, MD

Adrenocortical Excess

Cardiovascular Pulmonary Thromboembolism

II-1-68

Corinne L. Fligner, MD

Subdural Hemorrhage

II-1-96

Roy H. Rhodes, MD, PhD

Dylan V. Miller, MD

Myocarditis

II-1-12

II-1-100

Roy H. Rhodes, MD, PhD

Monica P. Revelo, MD, PhD & Dylan V. Miller, MD

Cardiac Conduction System

Subarachnoid Hemorrhage

II-1-18

Stroke

II-1-104

Hasini Reddy, MD, DPhil

Dylan V. Miller, MD

Aortic Dissection

II-1-24

Billie Fyfe, MD

Abdominal Aortic Aneurysm

II-1-30

Billie Fyfe, MD

SECTION 2 Postoperative/PostInterventional Death

Respiratory Pulmonary Edema

Iatrogenic II-1-32

Leslie A. Litzky, MD

Therapeutic Complications

II-2-110

Billie Fyfe, MD

Pulmonary Hemorrhage

II-1-36

Cardiovascular

Leslie A. Litzky, MD

Tension Pneumothorax

II-1-40

Leslie A. Litzky, MD

II-1-44

II-1-48 II-1-52

II-1-56

Thoracic Aortic Aneurysm Repair

II-2-132

Pancreas Resection

II-2-138

Rachel Hudacko, MD & Jeanine Chiaffarano, DO

II-1-60

Gastrectomy and Esophagectomy

II-2-142

Rachel Hudacko, MD & Jeanine Chiaffarano, DO

II-2-128

Gastrointestinal and Hepatobiliary

Rachel Hudacko, MD & Jeanine Chiaffarano, DO

Acute Liver Failure

Ventricular Assist Devices

Billie Fyfe, MD & George P. Batsides, MD

Hepatobiliary Hemorrhagic Pancreatitis

II-2-122

Brandon T. Larsen, MD, PhD

Rachel Hudacko, MD & Jeanine Chiaffarano, DO

Hepatic Hemorrhage

Valve Replacement (Including Transcatheter) Brandon T. Larsen, MD, PhD

Rachel Hudacko, MD & Jeanine Chiaffarano, DO

Intestinal Ischemia

II-2-118

Dylan V. Miller, MD

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Lower Gastrointestinal Hemorrhage

II-2-114

Dylan V. Miller, MD

Coronary Artery Stenting

Gastrointestinal Upper Gastrointestinal Hemorrhage

Coronary Artery Bypass Grafting

II-1-64

Bariatric Surgery

II-2-146

Rachel Hudacko, MD & Jeanine Chiaffarano, DO

Urosepsis

CNS Central Nervous System Tumors

II-2-150

III-2-64

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Roy H. Rhodes, MD, PhD

Cerebral Aneurysm and Vascular Malformation II-2-156 Roy H. Rhodes, MD, PhD

PART III

Neoplasia-Associated Death Death Due to Paraneoplastic Effect

SECTION 4 Other Common Hospital Death III-1-2

Dylan V. Miller, MD & Elizabeth H. Hammond, MD

III-1-8 III-1-12 III-1-22

Pancreas Transplant

III-1-28

Bone Marrow Transplant

III-1-32

Dylan V. Miller, MD

Deceased Donor Autopsy

III-1-36

Billie Fyfe, MD

SECTION 2 Infection-Related Death Systemic Infection/Sepsis Overview HIV/AIDS

III-2-38

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Shock and Sepsis

III-2-42

Billie Fyfe, MD & Christine Minerowicz, MD

Organ System Infection Bronchopneumonia

III-2-48

Leslie A. Litzky, MD

Infective Endocarditis

III-2-52

Dylan V. Miller, MD

Clostridium difficile Enterocolitis

III-2-56

Billie Fyfe, MD

Viral Hepatitis Rachel Hudacko, MD & Jeanine Chiaffarano, DO

xvi

III-2-60

III-4-86

Rachel Hudacko, MD & Jeanine Chiaffarano, DO

III-4-92

Monica P. Revelo, MD, PhD & Paisit Paueksakon, MD

Dementia and Neurodegenerative Disease

Monica P. Revelo, MD, PhD

III-4-82

Leslie A. Litzky, MD

Chronic Renal Failure

Rachel Hudacko, MD & Patrick Lento, MD

III-4-78

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

Chronic Liver Failure

Monica P. Revelo, MD, PhD & Paisit Paueksakon, MD

Liver Transplant

Chronic Obstructive Pulmonary Disease

Ventilator Dependent Respiratory Failure

Leslie A. Litzky, MD

Kidney Transplant

III-3-74

Harold Sanchez, MD, FCAP & Rebecca A. Irvine, MD, FRCPA

SECTION 1 Transplantation

Lung Transplant

III-3-68

Billie Fyfe, MD

Disease Process Approach to Autopsy

Heart Transplant

SECTION 3 Neoplasia-Associated Death

Hasini Reddy, MD, DPhil

III-4-100

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FYFE

MILLER

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SECTION 1

Introduction

History of Autopsy Autopsy Safety

I-1-2 I-1-6

Autopsy Fundamentals: Introduction

HISTORY OF AUTOPSY

Published in 1543, De Humani Corporis Fabrica was unprecedented for the accuracy of its descriptions, the beauty of its illustrations, and its bold emphasis on observation rather than tradition.

ANCIENT SOCIETY, DEATH REMAINS, AND MEDICINE Societal Attitudes Toward Human Remains Prehistoric societies may have had funeral rituals All known societies have rules for handling of the

dead Universal prohibitions against desecration of the dead No systematic study of internal anatomy in antiquity Advances in normal and pathologic anatomy occur in societies that promote and fund arts and sciences Governmental support is crucial No suspension of religious and societal customs possible without governmental support

Medicine in Antiquity

Prior to Greece: Health and disease depend on forces

I 1 2

outside of nature Healing intimately associated with religion Clinical examination and surface anatomy highly developed Knowledge of internal anatomy unimportant Biblical description (Hebrew tradition) Intimate knowledge of animal anatomy; sacrificial rites Cadavers "unclean" Obese King Eglon stabbed in abdomen "and the dirt came out" suggests some working knowledge, possible comparative to animals Frequent mention of flesh, sinews, bone, and marrow Greece and Hippocrates Medicine as natural science, not religious function Superb clinical observations, diagnosis, prognostication Good surface anatomy

Carl von Rokitansky (1804-1878), was a phenomenally prolific prosector and author who helped establish pathology as a separate medical specialty and helped make Vienna the medical capital of the world.

Virtually no human dissection; anatomy extrapolated from animal dissections Corpses ritually unclean; human dissection prohibited Humoral theory: Health depends on balance of 4 humors (blood, phlegm, black bile, yellow bile) Internal organs produce and circulate humors Knowledge of organ function largely speculative and somewhat fanciful Galen Expands and elaborates on humoral theory Anatomy based on dissections of pigs and Barbary apes Galen’s medical and anatomic works: Final authority for > 1,000 years Roman and Arabic physicians elaborate and comment on Galen without any thought of criticism Alexandria: Only exception to prohibition of human dissection in ancient world (300 BCE) Ptolemaic king establishes world’s largest library and museum; invites scholars Physicians permitted to dissect Physicians Herodotus and Erasistratus make remarkable advances in anatomy Lasted only a generation

ADVANCES TOWARD MODERN AUTOPSY PRACTICE Europe in Middle Ages

1213 CE: Holy Roman Emperor Frederick II permits

dissection on executed criminals in Salerno Medical School Students come to Salerno from across Europe Anatomy spread to schools in Italy (Padua, Bologna) and France (Montpellier)

When observed anatomy contradicted Galen’s anatomy, observation was largely ignored 1st European autopsies performed in 14th century Deaths in epidemics Questions of foul play (often in cases of suspected poisoning) Investigations into sainthood (search for miraculous findings, e.g., postmortem clots that resemble religious symbols) Role of coroner Established in 12th century England (Articles of Eyre) Duty to "keep the pleas of the crown" (protect financial interest of royalty in criminal proceedings) Role also defined in the Magna Carta Those who find deceased persons in suspicious circumstances must raise "hue and cry" to notify coroner

The Enlightenment

Andreas Vesalius: Professor of anatomy in Padua

De Humani Corporis Fabrica (1543): 1st book of human anatomy based on observation Errors of Galenic anatomy challenged; knowledge of normal anatomy improved Galenic humoral medicine continues uncontested Autopsies become more common High profile autopsies of monarchs (Henry II of France) and popes (Alexander V) Gradual increase in knowledge of pathologic anatomy Published collections of cases try to correlate clinical symptoms and pathological anatomy De Abditis (1507) by Antonio Benivieni: Hundreds of clinical cases, 20 autopsies De Sepulchretum (1679) by Theophilus Bonetus: 3,000 autopsy cases Giovanni Battista Morgagni De Sedibus (1761): Product of a lifetime of clinical practice and autopsies 646 cases with clinical records and autopsies organized by organ system; birth of clinical pathological correlation (CPC) Perhaps 1st pathology text

Paris School

French Revolution of 1790

Radical restructuring of French medical system Enormous public hospitals in Paris, Strasbourg, and Montpellier Huge numbers of patients concentrated in few places Physicians permitted to autopsy all charity patients dying in hospital Autopsy and clinical pathological correlation on unprecedented scale Foreigners from USA and across Europe study in Paris medical schools

2nd Vienna School

Holy Roman Emperor Joseph II provides funds for Allgemeines Krankenhaus (1784)

Law required all military, forensic, and hospital autopsies to be performed there (1818) Astronomical numbers of autopsies Karl Rokitansky: Performs 30,000 cases, supervises another 60,000 Apotheosis of autopsy gross pathology Autopsy and clinical pathological correlation at heart of academic medicine Rudolf Virchow and development of microscopy and cellular pathology Foreigners from USA and across Europe study in Vienna

Autopsy in USA

Autopsy Fundamentals: Introduction

HISTORY OF AUTOPSY

1910: Richard Cabot promotes case-based teaching with autopsy review Case records of Massachusetts General Hospital in New England Journal of Medicine Landmark paper on clinical diagnostic pitfalls revealed in 3,000 autopsy cases (1912) 1910 Flexner Report on American Medical Education Scathing indictment of American medical schools closure of 1/2 of existing schools Remaining schools adopt European model Scientific approach to medicine with autopsy/CPC as its centerpiece Academic clinicians and their teams expected to attend autopsy reviews Academic clinicians promote autopsy Hospital autopsy rate seen as measure of commitment to quality care By 1950s, average USA hospital rate ~ 50%; many hospitals with much higher rates

Decline of Hospital Autopsy

Post World War II: Federal funding for medical basic science research increases dramatically Academic pathologists focus on obtaining grants for research Autopsy not seen as way to further academic career Rise of surgical pathology and laboratory medicine Both pursuits are more time sensitive and more remunerative than autopsy pathology 1971: Joint Commission eliminates requirement for minimum hospital autopsy rate for accredited hospitals High rates of medical malpractice litigation Concern that autopsy findings could lead to lawsuits Improved imaging modalities: ability to detect pathological anatomy without autopsy 1974: 1st clinical CT scanner 1980: 1st clinically useful MR images 1986: Federal government eliminates direct reimbursement for autopsies Reimbursement for autopsy included in administrative budget Same part A reimbursement for 1 autopsy as for 100 Financial incentive to do fewer autopsies Average USA hospital autopsy rates estimated to be as low as 5-10%

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Autopsy Fundamentals: Introduction

HISTORY OF AUTOPSY Many community hospitals do few if any

Notable Autopsies in Medical History 1533: 1st autopsy in New World

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unlikely to change soon

Hispaniola: Conjoined twins survived 8 days Autopsy performed to determine if there were 1 or 2 children (and souls) 1724: Herman Boerhaave’s masterpiece of clinical pathological correlation Boerhaave attends gravely ill Admiral of Dutch fleet Meticulous case notes (including detailed inventory of preceding extraordinarily intemperate meal) Vomiting, pain, collapse Boerhaave’s autopsy findings: Esophageal rupture and mediastinitis 1859: Discovery of parathyroid glands Rhinoceros at London zoo dies after a week of vomiting Richard Owen performs autopsy Finds rib fractures with lung puncture Describes pea-sized gland attached to thyroid gland Ivar Sandstrom finds same glands in humans in 1880 1847: Pathologist Jacob Kolletschka dies of sepsis Cut himself during autopsy of woman with puerperal sepsis Obstetrician Ignaz Semmelweis notes similarities in autopsy findings in Kolletschka and women dying of puerperal sepsis Semmelweis realizes he and colleagues spread infection from morgue to obstetric patients Institutes 1st program of handwashing Clandestine autopsies About 1883: William Osler attends patient with Addison disease Family denies permission for autopsy Osler uses transanal approach to obtain adrenals 1910: Harvey Cushing attends patient with acromegaly Family denies permission for autopsy Cushing’s assistants bribe funeral director Harvest brain with pituitary gland moments before funeral ceremony

Proposed Alternatives to Traditional Hospital Autopsy Approach

CHALLENGES AND ALTERNATIVES

Current State of Autopsy

Autopsy rates despite literature demonstration of

Fewer cases for residents to learn from

Compelling financial and professional disincentives

continued effectiveness Autopsies still find significant diagnostic discrepancies Repeatedly documented in reports from Cabot in 1912 to Shojania and Burton in 2003 and beyond True even in cases with sophisticated laboratory and diagnostic imaging work-ups Death certification and vital records improve with higher autopsy rates Fewer autopsies loss of expertise Fewer pathologists with experience to teach

Regional autopsy centers

Single facility performs all medical autopsies for hospitals in large geographic region Concentrates numbers of cases and expertise Programs already exist at several medical examiners’ offices and academic hospitals Issues: Reimbursement, logistics, lack of interaction with clinical staff at originating hospital Radiographic or virtual autopsy (virtopsy) Pioneered in Switzerland Whole body CT or MR scan replaces traditional autopsy Allows excellent visualization of hard-to-dissect areas Overcomes religious objections to dissection Issues: Expense, availability, logistics, lack of histologic confirmation

SELECTED REFERENCES 1.

5. 6.

Hurren ET: Remaking the medico-legal scene: a social history of the late-Victorian coroner in Oxford. J Hist Med Allied Sci. 65(2):207-52, 2010 Pendleton C et al: The autopsy was conducted "Under most inauspicious circumstances:" John Turner, Harvey Cushing’s case XXXII, and his unwitting contributions to the early understanding of acromegaly. Pituitary. 13(4):324-8, 2010 Wright JR Jr: Sins of our fathers: two of The Four Doctors and their roles in the development of techniques to permit covert autopsies. Arch Pathol Lab Med. 133(12):1969-74, 2009 Hirt M et al: History of forensic medicine-the second part. The autopsy in the Middle Age and the Renaissance. Soud Lek. 50(3):32-7, 2005 Fu LK: Sung Tz’u (1186-1249) and medical jurisprudence in ancient China. J Med Biogr. 12(2):95-104, 2004 Shojania KG et al: Changes in rates of autopsy-detected diagnostic errors over time: a systematic review. JAMA. 289(21):2849-56, 2003 Mant AK: Forensic medicine in Great Britain. II. The origins of the British medicolegal system and some historic cases. Am J Forensic Med Pathol. 8(4):354-61, 1987 Goldman L et al: The value of the autopsy in three medical eras. N Engl J Med. 308(17):1000-5, 1983 King LS et al: A history of the autopsy. A review. Am J Pathol. 73(2):514-44, 1973

Evolution of the Autopsy (Left) Lecturer’s chair in the anatomic theater in Bologna: Prior to 1543, the professor of anatomy would sit above the dissection and read from a Galenic text while a prosector dissected. For centuries, discrepancies between the descriptions in the text and the structures in the body were simply ignored. (Right) Giovanni Battista Morgagni (1682-1771) helped establish derangements in normal anatomy as the cause of disease and put an end to centuries of medicine based on humoral theory.

Autopsy Fundamentals: Introduction

HISTORY OF AUTOPSY

(Left) Rudolf Virchow (1821-1902) brought microscopy into mainstream practice of pathology, and his Cellular Pathology (published in 1858) helped establish the cellular basis of pathology. (Right) The Allgemeines Krankenhaus in Vienna, home to some of the greatest figures in pathology & clinical medicine in Europe, attracted students from around the world and disseminated the use of clinical pathologic correlation as the cornerstone of medical education and practice.

(Left) The Bullfinch Building, Massachusetts General Hospital: After the 1910 Flexner Report, pathology assumed a central role in USA medical education. The Case Records of the MGH are an illustration of the continued educational power of the clinical pathological correlation. (Right) The autopsy remains a highly effective (if drastically underutilized) method for teaching medicine, improving the quality of patient care, and providing answers to family members.

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Autopsy Fundamentals: Introduction

AUTOPSY SAFETY

The resident in this photo is demonstrating the use of personal protective equipment with all body parts covered with waterproof apron and sleeves and eye and face protection .

TERMINOLOGY Definitions

Autopsy safety: Actions taken to protect prosectors and those present during the process of performing autopsy Involves being aware of pathogens, hazards, and risk Hazard: Potential source of harm or adverse health effect Types of autopsy hazards (Wetli): Mechanical, sharp force injury, electrical, chemical, radiation, infection Risk: Likelihood a person suffers adverse health effect if exposed to hazard High-risk autopsy: Autopsy where there is a high risk of transmission of disease to prosectors; most often confers risk of pathogen acquisition Pathogen: Any disease-producing agent, particularly virus, bacteria, parasite, or infectious particle (prion) Exposure to pathogen may be via blood/body fluid; inhalation; ingestion; direct inoculation; through mucous membranes of eyes, nose, and throat; and through breaks in skin barrier

SAFE AUTOPSY PRACTICES: REDUCING RISK Mechanical Risk Reduction

Risk includes injury from physical efforts such as lifting

Adequate staffing and equipment in autopsy suite to transport and transfer decedents helps reduce this risk

Sharp Force Risk Reduction

Risk includes injury from sharp tools or sharp edges at

I 1 6

autopsy (scalpels, cut ends of ribs)

Reduction starts with sharps awareness: Monitoring number of sharps being used at any time

Note the use of chucks as a protective barrier over the cut ends of the ribs. The nodular cirrhotic liver makes use of universal precautions mandatory.

Stop dissection if sharp (scalpel blade, saw blade, large or small knife, sharp tip scissors, sharp tip probe) is missing Scalpel blade removal: Use of hands-free devices instead of hands, forceps, or hemostats Prosector precautions Potential sharp hazards in body: Sharp rib edges or skull after sawing, edges of calcified vessels, wire sutures and meshes, and cut ends of metallic device leads Incising ribs through costochondral junction leads to naturally smooth surface, sharps risk

Electrical Shock Risk Reduction

Risk includes injury from electrical devices implanted in body such as automatic implantable cardioverter defibrillators Beware of implanted electrical devices within decedent, check chart, check externally for incisions over generator pockets, call device manufacturer (or local device) to deactivate implantable cardioverter defibrillators

Chemical Risk Reduction

Risk is potential injury from exposure to chemicals used during autopsy Formaldehyde/formalin is greatest risk Formaldehyde is mixture of formaldehyde gas and water Formaldehyde solution with 10-15% methyl alcohol = formalin Acute exposure effects include irritation to nose and eyes and mucous membranes Controversial carcinogenic effects of prolonged exposure Follow formaldehyde exposure monitoring policies of institution Use chemical hood for pouring large quantities of formaldehyde

Have access to chemical spill kit for formaldehyde spills

Radiation Risk Reduction

Risk is potential injury related to exposure to radiation from devices implanted in body Review chart for implanted radioactive devices (seeds): Type, distribution, duration ( duration radiation risk) If chart unclear but suspicion for presence of seeds, postmortem radiograph may reveal presence Seeds are radiopaque, ~ 4 x 8 mm Seeds may migrate from initial site (lungs, heart, etc.) Contact radiation safety officer for advice in cases of acute seed implantation or if other questions

Infection Risk Reduction

Risk is potential injury related to exposure to pathogens Use impervious barriers (personal protective equipment) and universal precautions meant to decrease risk of pathogen permeation through normal barriers such as skin, nasal membranes, eye and mucous membranes, and inhalation Universal precautions treat all body fluids as potentially infectious Personal protective equipment (PPE) Personal body coverings including gowns, masks or respirators, goggles, aprons, gloves, arm sleeves, and shoe covers meant to form a barrier against contamination in autopsy room Masks are a protective physical barrier meant to protect wearer from hazards such as splashes of blood and body fluids Keeps contaminated hands and fingers away from mouth and nose Respirators are protective equipment designed to decrease a prosector’s risk from airborne pathogen Prosector must be fitted to a respirator NIOSH (National Institute for Occupational Safety and Health) certified and used as part of comprehensive occupational health program Most often used in autopsies with risk of mycobacterial or influenza infection

High-Risk Autopsy Examples Mycobacterium tuberculosis

Occupational infection is usually pulmonary (90%) or cutaneous infection from inoculation (10%) Emergence of multidrug-resistant strains keeps M. tuberculosis an important pathogen to consider at autopsy Risk of tuberculosis to pathologists performing active tuberculosis autopsies is ~ 10%, from that of nonpathologist physicians Tubercle bacilli can be located from autopsy suite even 24 hours after postmortem examination Use of respirator (not mask) mandatory in cases of suspected M. tuberculosis Use of postmortem tissue culture or PCR to confirm diagnosis in suspect cases

Human immunodeficiency virus

Blood-borne pathogen with low seroconversion rate (0-0.42%) after occupational exposure Rate of HIV seroconversion after single percutaneous exposure with (1 L): 0.1-0.36% Mucocutaneous seroconversion rate: 0.04-0.63% Seroconversion risk relates to viral load in decedent, volume/nature of exposure, and underlying health of prosector and use of post-exposure prophylaxis Viral titers in patients expiring from terminal HIV are generally high Viral particles do not survive in blood exposed to environment outside body; they are inactivated by desiccation and disinfectants Blood and saliva testing has been shown to be reliable in postmortem setting but may require separate consent, so consultation with risk/legal services of institution advisable prior to testing Hepatitis virus Hepatitis B is very contagious, but preexposure vaccination has risk of occupational infection Hepatitis C is less contagious than hepatitis B, but there is no preexposure vaccination so risk of occupational infection is 2.7-10% Creutzfeldt-Jakob Disease (transmissible spongiform encephalopathy) Fatal human prion disease; can be acquired, but transmission to health care workers is rare Most institutions refer possible CJD autopsies to specialty centers Transmission by infected tissues and equipment (infected neurosurgical instruments and contaminated tissue implants/products) Most highly infectious tissue: Brain, dura mater, pituitary gland, spinal cord, posterior segment of eye, cranial and dorsal root ganglia, olfactory epithelium Prevention of aerosolization during brain removal is mandatory (wet cloth over saw, vacuum system, etc.) All higher infectivity tissue should be treated as such and appropriately labeled CJD resistant to alcohols and formols Fix infectious tissue in formaldehyde followed by formic acid for 1 hour Wash tissue again in formaldehyde prior to machine processing Instruments used for CJD autopsies should preferably be disposed of or dedicated to CJD cases with separate sterilization

Autopsy Fundamentals: Introduction

AUTOPSY SAFETY

SELECTED REFERENCES 1. 2.

3. 4.

Nine JS et al: Universal precautions and high-risk autopsies. Medscape. 2012 Flavin RJ et al: Mycobacterium tuberculosis at autopsy-exposure and protection: an old adversary revisited. J Clin Pathol. 60(5):487-91, 2007 Singleton M et al: The radioactive autopsy: safe working practices. Histopathology. 51(3):289-304, 2007 Burton JL: Health and safety at necropsy. J Clin Pathol. 56(4):254-60, 2003

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SECTION 2

Autopsy Performance

External Examination Medical Intervention Postmortem Changes and External Examination

I-2-8 I-2-12

Internal Examination Body Cavities Cardiovascular System Respiratory System Hematopoietic System Gastrointestinal System Hepatobiliary System Genitourinary System Endocrine System Central Nervous System Peripheral Nervous System Integumentary System Oral Cavity Medical Devices

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Laboratory Testing Chemistry Microbiology Cytology

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Postmortem Imaging Postmortem Radiography and Virtual Autopsy

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Autopsy Fundamentals: Autopsy Performance

MEDICAL INTERVENTION

A systematic approach to autopsy external examination is essential to avoid accidental omission of findings, particularly in complex disease processes when medical devices are numerous.

TERMINOLOGY Definitions

Medical interventions relevant to hospital autopsy external examination include all forms of health care intervention, regardless of Time when provided (recent or old) Timing relative to death (antemortem or postmortem) Site where provided (in hospital or elsewhere) Status of caregiver (physician, nurse, emergency medical technician, layperson, or otherwise) Type of intervention (noninvasive, invasive, or otherwise) Categories of medical intervention Recent vs. old Noninvasive vs. invasive indwelling device Antemortem vs. postmortem (organ and tissue procurement)

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Review decedent’s medical records in detail Past medical history Past surgical history Nonsurgical interventions Imaging findings Laboratory findings Events leading up to death Communicate with treating clinicians and surgeons Clarify intraoperative findings or complications Clarify specific questions to be answered Approach to external examination Systematic approach is essential to prevent accidental omissions "Clockface" approach: Begin by examining head (12:00), then proceed around table in a circle, examining left arm (3:00), left leg (5:00), right leg (7:00), right arm (9:00), and then finish by examining chest, abdomen, and back "Head to toe" approach: Begin by examining head, followed by arms, torso and back, and then finish by examining legs

CLINICAL IMPLICATIONS

Documentation of Findings

General Considerations

Monitoring pads or automated defibrillator pads Appropriate placement, shaving of body hair Recent surgical incisions Location, length, appearance, and adequacy of closure Old healed surgical incisions/scars Location, length, and appearance Indwelling tubes, catheters, and other devices Location, type, appropriate placement (to be confirmed upon internal examination) After documenting, external portions may be cut off if absolutely necessary, but internal portions should be left in place to facilitate evaluation of correct placement during internal examination Utilize a body diagram

Institutional policies and legal considerations

External examination provides clues to underlying diseases. Bandages and drains on legs suggest ischemic heart disease and saphenous vein harvesting for coronary artery bypass grafting.

All medical care items must be left on decedent’s body, and should not be removed prior to transfer of body to autopsy suite Deaths within 24 hours of admission to hospital fall under medical examiner’s jurisdiction in some states Deaths in emergency room, operating room, postoperative recovery room, &/or maternity ward also fall under medical examiner’s jurisdiction in some states Authorization for performance of autopsy ("autopsy permit") must be obtained and documented prior to performing autopsy Preparation for autopsy

Document all interventions in detail

If findings will be dictated later, write detailed notes Draw pictures of interventions Photography Essential for medical, legal, and educational purposes Usually best achieved with handheld, high-quality digital SLR camera Ensure adequate lighting; use flash or proper overhead lighting Include ruler and identifiers of decedent/case number in photograph Avoid distractions Obscure nonessential elements with drapes or blue towels Keep retracting hands and instruments out of photograph Frame shot close enough to visualize finding well, but far enough away that anatomic location and relationships are clearly discernible Clean away blood and body fluids Have a low threshold for photographing medical interventions: When in doubt, photograph! Reporting Utilize templates to prevent omissions Dictate external findings as soon as possible before details are forgotten After preliminary report is transcribed, review for accuracy as soon as possible

MACROSCOPIC FINDINGS General External Examination Standard measurements in adults

Height Weight Pupillary diameters Additional standard measurements in infants and young children Crown-heel length Crown-rump length Head circumference Chest circumference (at level of nipples) Foot length Interpupillary distance Head and neck findings Appearance relative to documented age Hair color and distribution Color of irides and sclerae Status of dentition (normal vs. partially or completely edentulous) In infants: Position of ears (low-set vs. normal), appearance of face (presence of abnormal facies), status of palate (clefted vs. normal) Any other abnormalities Other external findings Tattoos and distinctive piercings Abnormal skin coloration (e.g., cyanosis, jaundice) Ecchymosis Decubitus ulcers

In infants: Appearance of limbs (normal vs. dysmorphic), patency of anus, presence of Mongolian spot Any other abnormalities

External Evidence of Common Antemortem Interventions Noninvasive interventions

Bandages Electrocardiogram monitoring pads Automated defibrillator pads and burns Compression stockings/pneumatic compression devices Invasive interventions without indwelling device Venipuncture sites Surgical incisions (recent and old) Colostomy site (with colostomy bag) Amputations Invasive interventions with indwelling device Vascular access devices Intravenous catheters Arterial catheters Central venous catheters Intraosseous vascular access devices Extracorporeal membrane oxygenation (ECMO) cannulae Intracranial pressure monitoring catheter Nasogastric/orogastric tube Endotracheal/tracheostomy tube Pacemaker/defibrillator (AICD) Chest tubes Gastrostomy/jejunostomy tubes Surgical drains (e.g., Jackson-Pratt drain) Suprapubic catheter Foley catheter Epidural catheter

Autopsy Fundamentals: Autopsy Performance

MEDICAL INTERVENTION

External Evidence of Postmortem Interventions (Organ and Tissue Procurement) Internal organs

May include heart, lungs, liver, kidneys, pancreas, &/or intestines Surgical incision with simple crude closure Musculoskeletal tissues Bones often replaced with plastic rods Crudely closed surgical incision, with distortion of limbs (e.g., feet externally or internally rotated) Eyes (corneal tissue) Skin

SELECTED REFERENCES 1.

Rutty GN: The external examination. In: Burton JL et al: The Hospital Autopsy : A Manual of Fundamental Autopsy Practice. Boca Raton: CRC Press. 90-103, 2010 Finkbeiner WE et al: Basic postmortem examination. In: Autopsy Pathology: A Manual and Atlas. Philadelphia: Saunders Elsevier. 35-56, 2009 Waters BL: Ensuring quality in the hospital autopsy. In: Handbook of Autopsy Practice. New York City: Humana Press. 3-10, 2009

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Autopsy Fundamentals: Autopsy Performance

MEDICAL INTERVENTION

External Examination of Interventions (Left) Institutional policy should ensure that no medical devices are removed from the decedent prior to arrival in the autopsy suite, regardless of their nature or number. A systematic approach to external examination is essential to avoid accidental omission of findings and medical devices. (Right) Medical devices are common in the head and neck. Note nasogastric tube , tracheostomy tube , and multiple central vascular access catheters . Also note median sternotomy .

(Left) Old scars provide important clues. Note median sternotomy scar , suggestive of remote cardiac surgery (ascending aortic aneurysm repair). This decedent died of a dissecting aneurysm with fatal rupture 2 days after blunt force trauma to the abdomen (note contusions ). (Right) A large incision in the groin with ecchymosis suggests recent cannulation of femoral vessels with large-bore cannulae, as in this case of fatal H1N1 influenza requiring ECMO support.

(Left) The presence of a vacuum-assisted wound closure device ("wound vac") surrounded by erythema suggests the possibility of infection with sepsis. (Right) After removal of the wound vac, a large chest wall defect is visible, repaired internally with a membrane. The defect is surrounded by purulence , further suggesting infection. This patient died of bacteremia and sepsis 1 month after undergoing a chest wall resection for sarcoma.

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External Examination of Interventions (Left) This patient died after repair of a thoracoabdominal aortic aneurysm; clues regarding complications thereof are evident externally. Note colostomy bag , consistent with hemicolectomy due to bowel ischemia. Also note numerous recent, stapled surgical incisions . (Right) All evidence of intervention should be documented, regardless of perceived importance. Here, note arterial line , bandage , and puncture wound consistent with previous vascular access site.

Autopsy Fundamentals: Autopsy Performance

MEDICAL INTERVENTION

(Left) In some cases, external findings strongly suggest a disease process, even when details of the clinical history are unavailable. This patient developed leg ischemia (note red foot ) following repair of an abdominal aortic aneurysm, necessitating fasciotomy. Note blood-soaked bandage wrapping right leg . (Right) All bandages should be removed to expose tissues underneath. Here, 2 fasciotomy sites are readily identified, corresponding to bloodsoaked areas on bandages.

(Left) Skin removal is apparent on the lower arm of this decedent who required skin grafts elsewhere. Postmortem harvesting of skin would appear similar, but would lack bleeding . (Right) Postmortem interventions largely consist of organ/tissue harvesting for transplantation. Evidence thereof is readily apparent externally, as in this case where leg bones were harvested and replaced with plastic rods. Note crude closures and internally . rotated right foot

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Autopsy Fundamentals: Autopsy Performance

POSTMORTEM CHANGES AND EXTERNAL EXAMINATION

Loss of temporal muscle mass (bitemporal wasting) is a sign of marked wasting (cachexia) and may indicate underlying malignancy or chronic illness causing a malnourished state.

TERMINOLOGY Chapter Overview

This chapter will cover aspects of external

examination of body and changes that happen in postmortem state Traumatic and marked decomposition changes are not discussed as they are more relevant to forensic autopsies

Definitions

Postmortem interval: Time from death to start of postmortem examination Has important implications for degree of autolysis and ability to perform ancillary testing such as microbiologic and molecular studies

EXTERNAL EXAMINATION PROCESS Identification and Consent

Prior to autopsy, decedent identity must be confirmed, usually via wrist band, toe tag If question of identity, clarify before autopsy Consent must be reviewed prior to autopsy for accuracy and extent of examination

Postmortem Physical Exam (Inspection and Palpation) Head and neck

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Hair distribution (alopecia, male pattern baldness), length, and color Eyes: Iris color, pupil size and symmetry, sclera color (jaundice), conjunctival petechiae or pallor, edema, protuberant (thyroid ophthalmopathy), sunken (dehydration) Petechiae indicate hypoxia; pallor indicates anemia

Loss of muscle mass in the lower extremities also supports a diagnosis of cachexia. External examination can give important clues to underlying diseases, such as malignancy in this case.

Asymmetric pupils, markedly dilated may indicate CNS abnormality, drug effect, etc. (normal pupils: 1-8 mm) Nose: Discharge, ulcers, erosions Oral cavity Contents (gastric contents suggest terminal aspiration, blood), ulcers, erosions, masses Tongue size and appearance (e.g., thrush, atrophic glossitis, enlargement with amyloidosis) Tongue laceration (potential seizure disorder) Presence or absence of teeth and oral hygiene Face: Hirsutism, rashes, swelling and plethora (congestion), muscle wasting (bitemporal wasting), cachexia Marked facial swelling and plethora may indicate SVC syndrome; hirsutism may indicate Cushing syndrome Neck: Tracheal deviation, palpable adenopathy, enlarged thyroid Chest Shape: Barrel chested (emphysema), concave chest wall (pectus excavatum) Breasts: Shape, nipple appearance/discharge, palpable masses (include breast examination in male decedents) Gynecomastia in men: Consider age, chronic ETOH or marijuana exposure, antiandrogen, and other medications Abdomen Shape: Protuberant, concave If protuberant, check for fluid wave of ascites (place hands in a line along midline of abdomen, assistant taps 1 flank and checks for vibration on other flank) Striae If large purple striae with central obesity, consider Cushing syndrome Extremities

Edema, cyanosis, venous stasis, ischemic changes, ulcers, nail color and length and onychomycosis, muscular atrophy, myxedema Ischemic changes include thin shiny skin, hair loss, muscle loss; isolated ischemia to distal extremity digit may be embolic in origin (blue toe syndrome) Venous stasis changes include brown discoloration of skin and thickening of skin as well as mild edema Myxedema: Thickening of skin and subcutaneous tissue of lower extremities that is nonpitting and may be seen in thyroid disease Lower extremity edema is common and multifactorial; upper extremity edema usually in severe edema (anasarca) and isolated upper extremity edema may indicate SVC syndrome Back: Examination of the back is part of complete autopsy and must be performed Spine anatomy (scoliosis), decubitus ulcers, skin lesions, scars Anal area (warts, fissures, ulcers) Genitalia Male: Examine penis for lesions, discharge; scrotum for swelling, hernia, presence of testes Female: Vulva hair distribution, lesions (warts, ulcers), labia (warts, ulcers), vaginal discharge, ulcers/warts

Note any urine within reservoir (may be used for urinalysis; not good source for urine culture postmortem), any associated urethral edema or erythema Remember to deflate balloon prior to removal of catheter Chest tubes Examine location (note intercostal space from external exam, confirm on internal examination), any discharge Resuscitation-related changes These changes related to ACLS with defibrillation and CPR are almost ubiquitous in hospital autopsy practice Sternal bruising, palpable fractured ribs, and skin burning from defibrillator Surgical interventions Record incisions, extent of healing, implanted surgical devices, complications, etc.

Postmortem Changes General

Usually little decomposition in hospital autopsy practice; if body seems markedly autolyzed with appropriate temperature storage, consider sepsis Livor: Purple discoloration of dependent tissues due to pooling of blood in small vessels when circulation stops Portions of the body that rest against firm surfaces do not develop livor Develops within 30 minutes to 2 hours and becomes fixed (does not blanch when pressure is applied) at ~ 12 hours Tardieu spots are small petechiae that develop in areas of dependency Rigor: Tightening of muscles seen postmortem due to depletion of ATP; begins ~ 2-6 hours postmortem and begins in face and neck, affected by size of decedent and muscle mass, begins to pass within ~ 24 hours Rigor of erector pilae may led to postmortem goose bumps Decomposition: Describes process of autolysis of the body after death Green discoloration of right lower quadrant skin is early sign Purge fluid: Decomposition fluid that exudes from nasal and oral cavities

General

Height and weight must be recorded Skin elasticity, lesions, color, tattoos should be noted

Medical Intervention

Ideally, all medical devices/lines are left in situ when autopsy is to be performed and left intact after external examination to determine internal location If devices/lines have been removed prior to autopsy examination, it should be stated in the report Record location and placement of all devices (examples) Endotracheal tube (ETT): Length, how secured, associated trauma, placement, balloon inflation Intravenous/intraosseous lines: Note location and any associated erythema or swelling Central lines Location (chest, neck, groin), number of ports, any erythema, internal location of tip (radiograph may be warranted if question regarding central line placement) Pacer and AICD generators Note location of subcutaneous generator pockets and note skin erythema, evidence of infection If AICD generator is noted, prepare to deactivate device prior to internal examination (strong magnet overlying generator); contact institutional cath lab for specific information Nasogastric tube: Note location within nose Gastrostomy tube: Location, associated erythema around ostium, and location after internal examination Foley catheter

Autopsy Fundamentals: Autopsy Performance

POSTMORTEM CHANGES AND EXTERNAL EXAMINATION

SELECTED REFERENCES 1.

Zhou C et al: Factors and processes causing accelerated decomposition in human cadavers - An overview. J Forensic Leg Med. 18(1):6-9, 2011 Sauvageau A et al: Postmortem changes mistaken for traumatic lesions: a highly prevalent reason for coroner’s autopsy request. Am J Forensic Med Pathol. 29(2):145-7, 2008

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Autopsy Fundamentals: Autopsy Performance

POSTMORTEM CHANGES AND EXTERNAL EXAMINATION

External Examination and Postmortem Changes (Left) Examination of the oral cavity is important at autopsy. This patient had dentures, and there was some gastric content within the mouth focally adhering to the dentures . Terminal aspiration is frequently noted at autopsy. (Right) The redblue discoloration of these distal digits is due to ischemia and gives a clue to shock as a potential cause of death.

(Left) Livor mortis is purple discoloration due to the pooling of blood in dependent small vessels when circulation stops. Areas that are against a firm surface do not develop livor as noted by the pale area on the back of this decedent. (Right) This large area of green discoloration extending from the right lower quadrant is evidence of decomposition. This decomposition generally starts in the right lower quadrant due to the bacterial content in the cecum.

(Left) Corneal drying and clouding as demonstrated here are a common postmortem finding. (Right) There is marked pallor of the conjunctiva in this decedent related to marked anemia related to hemorrhagic shock.

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Postmortem External Features (Left) Postoperative cases, as demonstrated here, show evidence of multiple medical interventions. There is a recent large clamshell incision from axilla to axilla , a chest tube , and epicardial pacer lead wires . (Right) Another postoperative case demonstrates an endotracheal tube , orogastric tube , and central line . The length of endotracheal tube should be recorded as it exits the mouth (cm markings are on tube).

Autopsy Fundamentals: Autopsy Performance

POSTMORTEM CHANGES AND EXTERNAL EXAMINATION

(Left) There is a large sternal bruise present due to resuscitation attempts in this patient who also has evidence of a prior sternotomy scar . (Right) This decedent has a larger area of hematoma from resuscitation and an abrasion related to defibrillation.

(Left) All interventions should be noted. This patient had a gastrostomy tube present in the left upper quadrant. Removal of all bandages at external examination should be performed to be able to identify device insertions, wounds, etc. (Right) This PICC line is tunneled under the skin into the left subclavian vein. If there are questions regarding placement of PICC lines, radiography should be performed prior to internal examination.

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Autopsy Fundamentals: Autopsy Performance

BODY CAVITIES

The pericardial sac and epicardial surface from this patient with chronic renal failure show a characteristic, dull fibrinous "bread and butter" pericarditis.

TERMINOLOGY Definitions

Pericardial cavity

Normally ~ 50 mL of serous fluid

Pleural cavities

Estimated at up to 0.13 mL/kg of body weight Normally no more than 10 mL of serous fluid per pleural cavity Peritoneal cavity Normally 20 mL or less of serous fluid Divided into greater and lesser sacs May communicate with inguinal canal

EPIDEMIOLOGY

Gender

Acute Life-Threatening Compartment Syndromes

Particularly associated with breast and gynecologic tumors

ETIOLOGY/PATHOGENESIS Effusions

Imbalances in vascular function, fluid dynamics

content and low specific gravity; serous fluid CHF Cirrhosis Atelectasis Hypoalbuminemia Renal failure Exudates: Extracellular fluid rich in protein with high specific gravity Infections: Purulent pericarditis, empyema, bacterial peritonitis Inflammation: Asbestosis, pancreatitis, collagen vascular disease Malignancy Lymphatic abnormalities

CLINICAL IMPLICATIONS

2/3 of malignant pleural effusions occur in women

Transudates: Extracellular fluid with low protein

Incidence

~ 1.5 million cases of pleural effusion/year in USA

Fibrous pleural plaques are shown on the parietal pleural surface. These are benign pleural lesions that have been associated with exposure to asbestos.

Changes in permeability of mesothelial lining: Inflammation, malignancy Increased capillary hydrostatic pressure: Congestive heart failure (CHF) Decreased plasma oncotic pressure: Hypoalbuminemia, cirrhosis Capillary disruption: Trauma, malignancy, inflammation Blocked lymphatic drainage: Malignancy, trauma

All body cavities have more or less rigid boundaries Rapid accumulation of fluid, blood, air compromise of organ function and death Both volume and rate of accumulation influence outcome Pleural cavity Tension pneumothorax Pericardial cavity Pericardial tamponade Peritoneal cavity Abdominal compartment syndrome

Ascites

Ambulatory patients with cirrhotic ascites: 50% 3-year mortality

Patients with refractory ascites: < 50% 1-year survival

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BODY CAVITIES

rrss rrss MACROSCOPIC FINDINGS e e e e k k k k o o o o General Comments o o o o o o b b b b eebb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht Iatrogenic (i.e., central line placement)

Pneumothorax

Consider checking for pneumothorax before opening

the chest (potential causes: COPD, asthma, recently placed central line) Reflect the chest flaps (skin and subcutaneous tissue) laterally without entering pleural cavity Fill the pocket between flap and chest wall with water Create stab wound into pleura below the water level; look for bubbles or foam Fluid collections Measure and describe Opacity: Clear, cloudy, turbid, purulent Color: Straw colored, hemorrhagic, milky Ascites + right pleural effusion + benign ovarian tumor = Meigs syndrome Frank blood and clot Exclude artifact associated with autopsy procedure Try to identify source If obscure, consider en bloc (Rokitansky) evisceration Adhesions Describe: Fibrinous, fibrous, dense Correlate with clinical history and surgical absences

Spontaneous: Pulmonary blebs and changes of emphysema; changes associated with smoking Traumatic: Blunt or penetrating Catamenial: Secondary to pleural endometriosis Exclusively in women May have endometriotic implants in pelvis and abdomen Lymphangioleiomyomatosis Emphysema-like changes with cyst formation Usually in reproductive-age women Chylothorax Milky white, triglyceride-rich fluid Disruption or obstruction of thoracic duct or tributaries Malignancy: Especially lymphoma CHF: Accompanied by other signs of congestive failure Developmental anomalies (e.g., Down syndrome) Empyema Purulent exudate in pleural space Complication of pneumonia: Pneumonic changes in adjacent lung tissue Esophageal rupture (Boerhaave syndrome): Food and esophageal contents in pleural cavity, usually left sided Pleural plaques Tan white, firm, fibrotic plaques Especially near vertebrae, near lung bases, dome of diaphragm Associated with asbestos exposure Mesothelioma Tumor studding of pleural surfaces or continuous, plaque-like tumor covering pleural surfaces May be difficult to distinguish from lung cancer grossly Often associated with history of asbestos exposure

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Pericardial Cavity Serous effusions

Post myocardial infarction or myocardial trauma Collagen vascular disease Accompanied by other changes of underlying illness (rash, arthropathy, etc.) Hemopericardium Transmural myocardial infarction with rupture Aortic dissection/rupture Coronary artery dissection/rupture Trauma Pericardial rupture Traumatic; may be accompanied by other traumatic injuries Appropriately sized defects allow for cardiac herniation Pericarditis Infectious Fibrinous: Chronic renal failure ("bread and butter" pericarditis)

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Peritoneal Cavity Ascites

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / Pleural Cavity : : s s s s p p t t p p t t hhtt hhtt Serous effusions

CHF Pulmonary edema with heavy, congested lungs, dilated ventricles, pedal edema Parapneumonic Adjacent consolidated lung Malignant: ~ 40% of symptomatic pleural effusions Especially lung cancer, breast, lymphoma Primary effusion lymphoma in HIV/AIDS patients Hemothorax Chest wall trauma: Rib fractures, intercostal vascular disruption, aortic rupture Aortic dissection, aneurysm

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Benign May be associated with signs of cirrhosis (esophageal varices, splenomegaly) Malignant (e.g., associated with ovarian cancer or mesothelioma) Consider cytologic evaluation Peritonitis Infectious Associated with perforation in gastrointestinal tract Tuberculous: Numerous millimeter-sized nodules studding the peritoneum; usually part of disseminated infection Spontaneous bacterial peritonitis: Usually associated with cirrhosis and ascites; usually enteric bacteria Noninfectious Pancreatitis Extravasated urine (e.g., secondary to trauma) Ruptured dermoid cyst Collagen vascular disease

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Autopsy Fundamentals: Autopsy Performance

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Chylous ascites: Milky white, triglyceride-rich fluid

May be associated with abdominal trauma, tumors, cirrhosis, radiation therapy Hemoperitoneum Trauma: Blunt or penetrating Arterial aneurysm/rupture: Aorta, splenic artery Perforation/rupture of other structures: Gastric ulcer, intestinal tumor, hepatic tumor, ectopic pregnancy, corpus luteum Endometriosis Red-blue, "powder burn" lesions on peritoneal surfaces, especially pelvic peritoneum Lesions of intestinal serosa may fibrosis and obstruction Fibrotic lesions may mimic metastatic nodules Mesothelial cysts Often multiple, thin-walled, clear fluid-filled cysts Mesothelioma Tumor studding or diffuse plaques of tumor Pseudomyxoma peritonei Accumulation of mucinous fluid in peritoneum Associated with mucinous tumors of appendix and ovaries Hernias Protrusion of viscera and peritoneum beyond normal confines of abdominal cavity Common types Hiatal Abdominal wall: Ventral, postsurgical Inguinal, femoral Note presence or absence of incarcerated or infarcted bowel Internal hernia Protrusion of viscera through opening in peritoneum or mesentery within normal confines of abdominal cavity Loops of bowel may become incarcerated/ infarcted Through foramen of Winslow, paraduodenal, transomental; through cecal or sigmoid mesocolon Much less common than standard hernias Peritoneal carcinomatosis: Especially associated with ovarian cancer Primary peritoneal carcinoma Peritoneal carcinomatosis without identifiable primary source Histologically identical to ovarian serous carcinoma Ovaries uninvolved, minimally involved, or absent Peritoneal loose bodies (a.k.a. peritoneal MICE) Oval, 0.5-2.5 cm calcified Found free floating in abdominal cavity Thought to originate from torsed, detached appendix epiploica

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Single layer of mesothelial cells on basement

membrane Basement membrane with stomata that connect to lymphatics Allows passage of fluids, small and large molecules

Mesothelial cell response to inflammation, infection, other insults

Increased size of nuclei, nucleoli, mitoses, vacuolated cytoplasm Features may mimic malignancy (particularly in fluid cytology) Features favoring malignancy: Gross nodule formation, necrosis, stromal invasion

s r s r e e k k Mesothelioma o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht May be difficult to distinguish from metastatic carcinoma histologically

Types

Epithelioid: May mimic adenocarcinoma Sarcomatoid: Spindle cell tumor, may mimic sarcoma Biphasic: Epithelioid and sarcomatoid areas Immunoperoxidase stains are usually necessary for definitive diagnosis Positive in most mesotheliomas: CK 5/6, calretinin, WT1 Positive in most adenocarcinomas: Ber-Ep4, MOC-31, CEA Electron microscopy of mesothelioma Epithelioid tumors: Long, narrow, branching microvilli Lungs may show evidence of asbestosis Interstitial fibrosis Ferruginous bodies

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht Other Histologic Findings Endometriosis

Benign endometrial glands, endometrial stroma, hemosiderin Peritoneal cysts Thin-walled cysts with simple mesothelial lining Tuberculous pleuritis/peritonitis Characteristic granulomas with central caseous necrosis Acid-fast organisms on special stain Pseudomyxoma peritonei Rare islands of malignant cells floating in mucin

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t SELECTED REFERENCES hhtt hhtt 1. 2.

Visouli AN et al: Catamenial pneumothorax. J Thorac Dis. 6(Suppl 4):S448-60, 2014 Dubeau L et al: Coming into focus: the nonovarian origins of ovarian cancer. Ann Oncol. 24 Suppl 8:viii28-viii35, 2013 Fede G et al: Renal failure and cirrhosis: a systematic review of mortality and prognosis. J Hepatol. 56(4):810-8, 2012 Noppen M: Normal volume and cellular contents of pleural fluid. Curr Opin Pulm Med. 7(4):180-2, 2001

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Lines all body cavities and produces scant serous fluid

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Autopsy Fundamentals: Autopsy Performance

BODY CAVITIES

rrssFeatures Gross e e k k o o o o eebb

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht (Left) This in situ photograph shows the pericardium folded back from the epicardium to reveal a greenyellow purulent pericarditis . These are most often bacterial and originate from either infections in contiguous structures or bloodstream infections. (Right) The parietal pleural surface is completely covered by tiny tan-white nodules , a characteristic appearance for tuberculous pleuritis. The nodules are often below the resolution of imaging techniques.

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) The abdominal cavity normally has 20 mL or less of serous fluid. These containers hold the mucoid contents from the peritoneal cavity of a patient with a mucinous ovarian tumor, a condition know as pseudomyxoma peritonei. (Right) This segment of peritoneum shows a dark gray-black, "powder burn" discoloration, characteristic of peritoneal endometriosis .

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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(Left) This in situ photograph shows a thick, tan-white pleural-based tumor that covers much of the exposed parietal pleura. Microscopy with immunoperoxidase was diagnostic of mesothelioma. (Right) This external photograph shows a massive inguinal hernia . Such hernias may contain most of the small and large bowel as well as omentum. They are associated with impaired mobility, possible bowel obstruction, and scrotal ulceration.

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt CARDIOVASCULAR SYSTEM

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s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hhtFINDINGS hht MACROSCOPIC This illustration shows cardiac anatomy in the (parasternal) long axis view. The mitral valve and aortic valve are seen in this plane, as is the left ventricular myocardium .

External Examination

Accurate body height and weight important for

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This corresponding gross photograph of an autopsy heart cut in long axis shows the mitral leaflets and aortic valve . The left ventricle is hypertrophied .

Cut through pulmonary veins on both sides, taking care not to disrupt left atrium Cut through any remaining pericardial attachments to free heart specimen Heart Remove/strip parietal pericardium Note position and patency of proximal coronary arteries, any vein grafts Section each coronary artery at 5 mm intervals and estimate cross-sectional area stenosis Coronary arteries may be examined in situ or after removing by dissection (decalcification may be needed, stented segments may need special processing) Combined short-axis and inflow-outflow technique Cut 3 or 4 slices (1 cm thick) in short axis through ventricles (parallel to posterior/inferior coronary groove, stopping at mid papillary muscle level) Inspect ventricular myocardium for mottling, scars, rupture, etc. Using scissors, incise right atrium from IVC to tip of appendage Inspect right atrium for patent oval foramen, coronary sinus ostial obstruction, etc. Using long blade, cut through atrium, tricuspid anulus, and ventricle, along posterior septum Unfold ventricle to inspect tricuspid valve and measure its circumference Using scissors, cut right ventricle anteriorly out through pulmonary valve Unfold ventricle in this plane to inspect pulmonary valve and measure its circumference Using scissors, incise left atrial appendage tip and cut along left atrium just above mitral annulus Inspect left appendage for clot Using long blade, cut through left atrium, mitral anulus, and ventricle, in between papillary muscles

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t ht hht General Featuresh calculating expected heart weight

Surgical scars

Median sternotomy or other thoracotomy Midline abdomen (abdominal aortic aneurysm repair) Vein harvesting sites Dialysis fistula (hypertension) Pacemaker pocket, other implantable devices Edema, ascites (congestive heart failure)

Prosection

Removed en bloc with lungs Remove chest plate, taking care to preserve any internal mammary artery grafts Just below thoracic inlet, cut through trachea, esophagus, and aortic arch vessels Using caudal traction on trachea, cut through posterior pleural reflections, following along vertebral bodies, to diaphragm Lift heart from diaphragm where IVC enters right atrium Cut IVC and remaining attachments tethering thoracic organ block Follow piecemeal instructions below Removed piecemeal Open pericardium and measure fluid (normal ~ 50 cc), note any adhesions Open main pulmonary artery for saddle embolus inspection (optional) Cut great arteries (aorta and pulmonary artery) 2 cm above ventricles Lift apex of heart, putting tension on pulmonary veins

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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: s s p t p t hhtt

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Unfold ventricle to inspect mitral valve and measure its circumference Cut through left ventricle anteriorly through outflow tract and aorta Unfold ventricle in this plane to inspect aortic valve and measure its circumference Four-chamber This view shows relation of atria, ventricles, and atrioventricular valves Best performed with long, sharp knife Begin at cardiac apex Proceed along plane defined by: 1) apex, 2) acute margin of right ventricle, and 3) inferior/posterior obtuse margin of left ventricle; pins may be placed to mark this plane Extend cut into mitral and tricuspid valves and through atria Knife should end 1 cm posterior to roots of great arteries Long-axis method This view shows anterior mitral leaflet-aortic continuity with mitral inflow and aortic outflow tracts on either side Best performed with long, sharp knife Begin at cardiac apex Proceed along plane defined by: 1) apex, 2) right aortic sinus of Valsalva, and 3) mitral valve annulus midway between right and left pulmonary veins; pins may be placed to mark this plane Extend cut through right ventricular outflow tract (in cross section) and aorta (in longitudinal section) Thoracic aorta Beginning at proximal arch, cut posteriorly along line ~ 1 cm posterior to arch branches Continue to descending thoracic end Inspect for atherosclerosis (assess % surface area and note any calcification or ulceration) or dissection Open each arch vessel and visually inspect intercostal branch ostia Abdominal aorta Beginning proximally, cut along line posteriorly, just to one side of intercostal branches Continue through one of the iliac branches to end; then, starting at bifurcation, cut through other iliac Inspect renal arteries, celiac axis, superior and inferior mesenteric and other branches Inspect renal artery stenosis or fibromuscular dysplasia Inspect for atherosclerosis (assess % surface area and note any calcification or ulceration) or aneurysm

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Autopsy Fundamentals: Autopsy Performance

CARDIOVASCULAR SYSTEM Infero-septal and right ventricle (posterior descending) Right dominant (RCA), left dominant (LCX) Careful evaluation of entire coronary tree in cross section In situ or after dissecting free from heart Decalcification may be necessary Document interventions (stents, bypasses)

Left ventricle internal short-axis diameter > 5.0 cm Mitral annular circumference often > 10.5 cm Right ventricle may be secondarily enlarged Exclude ischemic disease Clinically exclude Chronic ethanol abuse Hemochromatosis Familial

s r s r e e k k o o o o o o b b b b e e / / e e / / e e Sudden Cardiac Death e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht Determine if heart is "structurally normal" Exclude conditions associated with acute arrhythmia

Arrhythmogenic cardiomyopathy Hypertrophic cardiomyopathy Coronary artery obstruction Myocardial scarring (ischemia, old myocarditis) Myxomatous mitral valve disease (mitral valve prolapse) Acute myocarditis Coronary artery anomalies Consider examination of conduction system

s r s r e e k ook o o o o b b b b e e / / e e / SPECIAL STUDIES / e e e e m m . . m m t t . . / / t t / / / / : : Tetrazolium Chloride Incubation for / / : : ss ssInfarction p p t t Detection of Acute Myocardial p p t t t t hht hht 2 common tetrazolium salts used: Nitro blue (BBT)

and triphenyl tetrazolium (TTC) Viable tissue with intact dehydrogenase activity reduces solution to colored formazan salt: NBT blue and TTC red Results: Infarct unstained, viable tissue blue (NBT) or red (TTC), scar white Technique includes dilution of tetrazolium salt in buffered solution and incubation of fresh slides myocardium at 37 C; usually 30 min until color develops Fix myocardial slice in formalin to aid contrast between viable and infarcted tissue

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt SELECTED REFERENCES 1.

Kakimoto Y et al: The effectiveness and limitations of triphenyltetrazolium chloride to detect acute myocardial infarction at forensic autopsy. Am J Forensic Med Pathol. 34(3):242-7, 2013 Basso C et al: Guidelines for autopsy investigation of sudden cardiac death. Virchows Arch. 452(1):11-8, 2008 Edwards WD. Cardiac anatomy and examination of cardiac specimens. In: Damjanov et al. Anderson’s Pathology, 10th ed. CRC Press: Kansas City. 80-117, 1995

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Segmental evaluation of short-axis ventricle sections, according to coronary territory Antero-septo-lateral (LAD) Lateral (LCX)

2. 3.

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt CARDIOVASCULAR SYSTEM

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s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Gross Features

(Left) Illustration shows the heart viewed posteriorly. From this perspective, all of the attachments that must be cut during prosection can be viewed, including the inferior and superior vena cava , the pulmonary veins , and great arteries . (Right) Gross photograph of the pericardial sac after heart removal also shows the connections: Vena cava , pulmonary veins , and great arteries . (Courtesy W.D. Edwards, MD.)

(Left) Heart removed at autopsy is viewed anteriorly, with the superior vena cava , aorta , and pulmonary artery serving as landmarks. Short-axis ventricle sections should be cut, roughly along the dashed lines; running parallel to the coronary (atrioventricular) groove. (Right) This right lateral view of the heart (with superior and inferior vena cava, and right atrial appendage ) shows how short-axis sections should be cut parallel to the coronary groove .

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s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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(Left) Short-axis section of an autopsy heart shows marked concentric left ventricular hypertrophy . The right ventricle size and wall thickness is relatively normal. (Right) Short-axis view of an autopsy heart shows features of dilated cardiomyopathy. The left ventricle wall thickness is relatively normal, but the left ventricular chamber is dilated (diameter > 5 cm). There are no scars to suggest an ischemic etiology. The right ventricle is dilated as well.

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Autopsy Fundamentals: Autopsy Performance

CARDIOVASCULAR SYSTEM

rrssFeatures Gross e e k k o o o o eebb

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht (Left) This autopsy heart, viewed in short axis, shows acute myocardial infarction with myocardial mottling . A fibrin-lined rupture tract is also visible in the free wall. (Right) This shortaxis ventricular section is from an autopsy of a patient with longstanding ischemic cardiomyopathy. A large anterior wall old infarction is seen. There has been extensive remodeling, with dilatation and wall thinning. There is also compensatory hypertrophy in the viable myocardium .

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) The right atrial structures can easily be examined after short-axis ventricle sections are cut. This view with the tricuspid valve annulus opened shows the oval fossa , superior vena cava , and coronary sinus ostium . (Right) The left atrial structures are also easily viewed in this dissection method, as in this autopsy heart specimen from a patient with rheumatic mitral valve disease. The limbus remnant of the oval fossa and pulmonary vein orifices are shown.

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s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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(Left) The origin and course of the coronary arteries should be documented at autopsy. These include the right , left anterior descending , and left circumflex coronary arteries. (Right) The coronary arteries are best evaluated in cross section, either in situ or after removal from the heart. In this cross section of the left anterior descending artery, there is is significant luminal obstruction as well as gross evidence of intraplaque hemorrhage .

Autopsy Fundamentals: Autopsy Performance

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: s s p t p t hhtt RESPIRATORY SYSTEM

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hhtFINDINGS hht MACROSCOPIC This is a normal and appropriately expanded right lung that adequately fills the thoracic cavity (chest wall ). The pleural surface is glistening, and a small amount of anthracotic pigment is noted.

General Features

Right lung consists of 3 lobes: Right upper, right

The cut section shows grossly normal lung parenchyma with alveolar spaces imparting a spongy appearance to the parenchyma.

Main pulmonary artery divides in front of left mainstem bronchus into right and left pulmonary arteries Right superior, right inferior, left superior, and left inferior pulmonary veins drain into left atrium Mediastinal, hilar, and intrapulmonary lymph nodes are easily identified by presence of anthracotic pigment deposition Some anthracotic pigment deposition is typical of most urban/suburban populations Marked anthracotic pigment deposition is seen in smokers, recreational inhalation drug users (especially crack cocaine), industrial/mining occupations, and in regions where cooking over open fire (particularly in a closed space) is customary Slightly enlarged subcarinal lymph nodes are common finding at autopsy and usually of no significance

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middle, and right lower Horizontal fissure (or minor fissure) separates right upper and right middle lobes Oblique fissure (or major fissure) separates right middle and lower lobes Left lung consists of 2 lobes: Left upper and left lower, plus lingula, which is rudimentary appendage that arises from left upper lobe Oblique fissure (or major fissure) separates left upper and lower lobes Each lobe is further divided into bronchopulmonary segments, each supplied by its own segmental bronchus Segments are further divided into lobules Lobule consists of multiple pulmonary acini, bound by connective tissue (interlobular septa) Each lobule is 1-2 cm in diameter and can be identified on high-resolution CT scans Lobules are also grossly visible from pleural surface of lung or on cut surface because of their septal demarcation A number of pathologic processes may accentuate lobular architecture, including fibrosis, inflammation, or blood accumulation Lung has dual blood supply Bronchial arteries are derived from systemic circulation, most often from thoracic aorta Supply blood to airways to level of respiratory bronchioles and to connective tissues of lung However, there is variation, particularly on right side Pulmonary arterial circulation receives deoxygenated blood via right ventricle where it is oxygenated at level of alveolar microvasculature and returned to left atrium

Specimen Handling

Cutting lungs in a fresh state enhances appreciation

of some pathologic processes (e.g., pulmonary edema) and may be appropriate in some circumstances Formalin perfusion of lung and fixation allows for better overall appreciation of many other pathologic processes such as infection, parenchymal disease, and malignancy, many of which coexist in hospital autopsy population Formalin perfusion is therefore recommended Sequence of evaluation is extremely important External examination of thorax for lines, chest tubes, surgical sites, symmetry, tracheal deviation, muscular/bone abnormalities, and skin lesions Following standard Y-shaped incision and reflection of skin and subcutaneous tissue from bony thorax, test for pneumothorax if clinically appropriate Following removal of chest plate, assessment should continue with

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Autopsy Fundamentals: Autopsy Performance

RESPIRATORY SYSTEM

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Presence, quantity, and character of fluid in pleural space Presence of adhesions and other parietal/visceral pleural lesions Thoracic surface of diaphragm and its appropriate position should be included Description of lung volumes Common terms used to characterize deviation from normal lung volumes Hyperinflation (lungs may meet in midline of anterior mediastinum) Compression atelectasis (partial/complete, unilateral/bilateral) due to fluid, air, or tumor Contraction atelectasis due to pulmonary or pleural fibrosis Decrease in size due to hypoplasia (most commonly seen in neonatal and pediatric populations) Procurement of fresh tissue for microbiology cultures or other special studies Assessment for saddle embolism prior to separation of right and left pulmonary arteries from main pulmonary artery and heart Complete gross inspection of surfaces of lungs and palpation following removal from thoracic cavity and detachment from heart and mediastinal structures Obtain lung weights prior to formalin perfusion Formalin perfusion either through mainstem bronchi or trachea with attached lungs, depending on circumstances Although rarely used in daily practice, it is possible to perfuse lungs through pulmonary arterial system Following removal of thoracic organs, chest wall and parietal pleura should be reinspected (plaques, adhesions, etc.) Sectioning of lungs following perfusion and fixation Fixed lung is firm and easy to slice thinly for optimal gross examination In any plane of sectioning, slices should be no thicker than 2 cm, and all larger airways and vessels should be opened with scissors if incompletely cut Even with these thin sections, one must palpate lung slices thoroughly in order to identify and localize radiographic abnormalities (normally visualized radiographically down to ~ 0.5 cm) or smaller unsuspected lesions Parasagittal (slab) sectioning demonstrates lung from apex to base; lobar demarcations are well seen Lung is serially sectioned with lateral pleural surface down on cutting board and hilar region facing up, thus distinguishing more central regions from periphery Important, as many pathologic processes in lung are characterized by preferential distribution of upper lobe predominant vs. lower lobe predominant or central vs. peripheral Transverse sectioning is useful if close CT correlation is indicated

Liebow bronchial probe technique is alternative method when, for example, clinical history suggests a primary pulmonary malignancy Probes are passed down airways and used as a guide for slicing Resulting cuts are in neither sagittal nor coronal plane, but technique is excellent for demonstrating relationship of tumor to airway Mediastinal and hilar/intrapulmonary lymph nodes sections are generally recommended depending on clinical circumstances and pulmonary findings

Anatomic Features

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s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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Some normal anatomic variations and common

clinically insignificant abnormalities may be identified, particularly in older patients Apical fibrosis, often bilateral (a.k.a. apical cap) Previously believed that this apical fibrosis represented healed tuberculosis Now thought to represent a localized scarring of subpleural parenchyma due to relative underperfusion of apices Focal scarring and chronic inflammation are also common at lobar tips, particularly in middle and lower lobes

MICROSCOPIC FINDINGS

General Features

Bronchi are cartilaginous airways, usually > 1 mm in

diameter Bronchi conduct air, and presence of cartilage in their walls helps to prevent airway collapse Cartilaginous plates (both in bronchi and trachea) may calcify with aging Normal finding in older patients Bronchial mucosa consists of surface epithelium, which rests on a basement membrane and elastinrich layer of connective tissue below it Submucosa is beneath mucosa and includes submucosal glands, cartilage, nerves, ganglia, and branches of bronchial artery Boundary between mucosa and submucosa is not well defined histologically Beyond submucosa, there is loose peribronchial connective tissue that is contiguous with pulmonary artery Pseudostratified columnar epithelium includes numerous ciliated columnar cells with less frequent interspersed mucous (goblet) cells, as well as scattered and often inconspicuous neuroendocrine and basal cells Goblet cell metaplasia (generally but not precisely defined as ~ 10 or more goblet cells in a row) is very common finding in smokers and in other patients with chronic airway diseases As airways become smaller, there is progression from pseudostratified ciliated columnar epithelium to a more cuboidal epithelium

Autopsy Fundamentals: Autopsy Performance

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: s s p t p t hhtt RESPIRATORY SYSTEM

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s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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s r s r e e k ook o o o o b b b b COMMON RESPIRATORY SYSTEM e e / / e e / PATHOLOGY AT AUTOPSY .m / e e e e m . m m t t . . / / t t / / / / : : / / Bronchopneumonia : : ss ss p p t t p p t t t t hht hht

Bronchioles are membranous airways without

cartilage in their walls and are usually < 1 mm in diameter Terminal bronchioles are nonrespiratory bronchioles just proximal to respiratory bronchioles Respiratory bronchioles have alveoli budding from their walls Lambert canals are direct communications between nonrespiratory bronchioles and alveoli Inconspicuous under normal conditions but become more prominent in scarred airways when surrounded by metaplastic bronchiolar epithelium (a.k.a. peribronchiolar metaplasia, lambertosis, or bronchiolarization) Peribronchiolar metaplasia is not a normal finding and can be seen in a number of diffuse lung diseases Acinus is functional unit of gas exchange One definition of acinus is a single terminal bronchiole and pulmonary parenchyma distal to it Others define acinus as a single respiratory bronchiole and all alveolar ducts and sacs distal to it Alveoli have thin walls containing rich capillary network (pulmonary microvasculature) Many nuclei that appear most obvious on routine microscopic sections of alveoli are endothelial cell nuclei Alveoli are lined by flat squamous type I pneumocytes Cuboidal type II pneumocytes, which produce surfactant, are fewer in number Although not specific to etiology, type II pneumocyte hyperplasia indicates reparative response to alveolar injury A few scattered intraalveolar macrophages are normal in lung Pigmented pulmonary macrophages are greatly increased in smokers (respiratory bronchiolitis) as are Langerhans-type macrophages (S100, CD1a positive) Although not specific to etiology, hemosiderinladen macrophages indicate prior presence of blood within alveolar spaces; etiologies include Chronic outflow obstruction (most commonly due to cardiac disease and quite rarely due to pulmonary venoocclusive disease) Diffuse alveolar hemorrhage Localized alveolar hemorrhage secondary to any number of causes such as infection, infarction, vasculitis, and malignancy Large pulmonary arteries are elastic arteries Elastic fibers are relatively prominent until level of bronchi branching into bronchioles At level of bronchioles, pulmonary arteries become primarily muscular arteries with well-defined internal and external elastic lamina As pulmonary arteries become smaller, double elastic lamina is replaced by single elastic lamina, making a distinction from venules more difficult Pulmonary veins have single lamellated elastic lamina

Small intraacinar pulmonary veins merge into larger pulmonary veins within interlobular septa Identification of pulmonary vasculature under normal and pathologic conditions rests on these defining microscopic features and vessel location, with location being more reliable of the 2 criteria under certain conditions, such as pulmonary hypertension Some degree of pulmonary arteriole hyalinization, as well as pulmonary arterial and venous intimal thickening, is seen in aging individuals Visceral pleura is composed of outer mesothelial layer (which is easily denuded by mechanical manipulation and autolysis) with underlying connective tissue layered between 2 elastic lamina layers, and connective tissue layered at interface with alveolated parenchyma In some instances, these elastic layers are distinct, and in other instances, elastic fibers are less well organized Although common and not always specific to etiology, any thickening beyond these 5 layers indicates reactive response to injury There is lymphoid tissue associated with airways (bronchial-associated lymphoid tissue [BALT]) Otherwise, lymphoid tissue should be sparse or inconspicuous under normal conditions Lymphatics run within bronchovascular bundles and pulmonary veins within septa and pleura There are no lymphatics within alveolar walls

Lungs are consolidated usually in patchy distribution and heavy with polymorphonuclear leukocytes and fibrin within airways and alveoli

Diffuse Alveolar Damage

Diffusely consolidated and firm heavy lungs with

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s r s r e e k ook Edema o oo Pulmonary o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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intraalveolar hyaline membranes with variable organization

May be noncardiogenic (diffuse alveolar damage) or

more commonly cardiogenic at autopsy Cardiogenic pulmonary edema with increased weight, congestion, and often frothy fluid in airways and microscopic alveolar capillary congestion and intraalveolar, pink-appearing edema fluid

SELECTED REFERENCES

2. 3.

Leslie KO et al: Lungs. In Mills S: Histology for Pathologists. 4th ed. Philadelphia: Lippincott Williams & Wilkins. 505-39, 2012 Murali R et al: The pleura in health and disease. Semin Respir Crit Care Med. 31(6):649-73, 2010 Van Der Spuy JC: The surgical anatomy of the pulmonary vessels. Thorax. 8(3):189-94, 1953

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: s s p t p t hhtt Autopsy Fundamentals: Autopsy Performance

RESPIRATORY SYSTEM

rrsDissection rrss s Lung Technique e e e e k k k k o o o o o o o o o o b b b b eebb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

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(Left) The pericardial sac is open, and the heart is lifted up to reveal the pulmonary veins as they empty into the left atrium. (Right) The pericardial sac is open, the heart is lifted up , and the pulmonary veins have been cut to expose the pulmonary artery. The main pulmonary artery has been opened and is being checked for a pulmonary embolus in the left pulmonary artery .

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) The slab method of whole lung sectioning is illustrated here. The hilar region is facing up , and the knife is used to cut a full parasagittal section from apex to base. The slices should be 2 cm in thickness. (Right) The next step in the slab method of whole lung sectioning is illustrated here. After the initial cuts, scissors must be used to open up partially cut airways and vessels for a complete examination.

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s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

(Left) The bronchial probe technique for sectioning the lung is demonstrated. Two probes have been inserted into the mainstem bronchus and used as a guide for sectioning . (Right) The post probe section shows the bronchial anatomy . Also note how well a hilar lymph node is exposed .

Autopsy Fundamentals: Autopsy Performance

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: s s p t p t hhtt HEMATOPOIETIC SYSTEM

rrss e e k k o o o o eebb

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t ht hht DEFINITIONSh DISSECTION Metastasis to bone is a common complication of epithelial tumors, especially breast, prostate, and lung. This in situ image shows the lumbar vertebral column with the anterior 1/2 removed.

Hematolymphoid Tissue Lymph nodes

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Lymph Nodes

Note presence and distribution of any

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Normally discrete, < 1 cm greatest dimension Extranodal hematolymphoid tissue Upper aerodigestive tract: Waldeyer ring Tonsils: Pharyngeal, palatine, tubal, and lingual Typically inaccessible during standard autopsy Thymus Located in anterior mediastinum Readily identified in infants and young children Usually regresses afterwards; not typically found in adults Bronchial-associated lymphoid tissue (BALT) Gut-associated lymphoid tissue (GALT) Intraepithelial lymphocytes: Predominantly Tcells Intramucosal lymphoid aggregates Peyer patches Mesenteric lymph nodes Spleen Normal weight approximately 150 grams; 10-11 cm in greatest dimension Bone marrow Red marrow: Relatively more hematopoietic tissue, less fat Confined to axial skeleton in adults Found in all bones in infants Yellow marrow: Relatively less hematopoietic tissue, more fat Peripheral blood Examine smears of premortem samples retrieved from hospital laboratory if available

s r s r e e k ook o o b eeb

Splenomegaly may be caused by a wide variety of causes (portal hypertension, infection, hematologic disorders). Shown here is a spleen largely replaced by metastatic lung cancer.

lymphadenopathy Palpate for superficial (cervical, supraclavicular, axillary, inguinal) adenopathy Sample any enlarged or otherwise grossly abnormal nodes Consider touch prep cytology/frozen section to guide work-up Suspicious for lymphoma: Save fresh tissue in appropriate cell culture medium for flow cytometry Suspicious for infection: Submit tissue for culture

Spleen

Note appearance of capsule, color, size, weight

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / Bone Marrow / / : : / / : : s s s s p p t t p p t t hhtt hhtt Massive splenomegaly: Spleen tip extends across midline, into left lower quadrant, or into pelvis Take culture in cases of suspected sepsis Serially section, note appearance of cut surfaces Submit section of normal spleen and other sections as needed

After evisceration, use saw to cut off anterior aspect of lumbar vertebrae

Note color of bone marrow, presence or absence of masses

Shave off a thin slice from exposed marrow, fix,

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HEMATOPOIETIC SYSTEM

rrss rrss e e e e k k k k o o o o o o o o o o b b b b eebb Special Procedures e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: Lymph Nodes, Selected Neoplastic p p t t p p t t t t hht hht Conditions Smears and bone marrow biopsies can be performed from posterior superior iliac spine as in living patients using bone marrow biopsy needle

Note: Complete hematopathologic evaluation may

not be possible Some procedures require viable cells Cost of some procedures may be a barrier in autopsy setting Immunoperoxidase Usually readily available Tissue should be well preserved but need not be viable Along with histology and clinical picture, often enough to establish diagnosis Flow cytometry: Unlikely to work on postmortem tissue unless postmortem interval is short In some cases (e.g., suspected leukemia), peripheral blood flow cytometry is useful Obtain premortem blood from clinical laboratory if available Cytogenetics: Requires viable cells; unlikely to yield results on autopsy tissue

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Granulomas may extensively replace nodes Typically in mediastinal and peribronchial nodes Rheumatologic diseases May be associated with lymphadenopathy Other signs of connective tissue disorder often present (e.g., rash in systemic lupus erythematosus, arthritic changes in rheumatoid arthritis)

Note: Definitive diagnosis in some cases may

require clinical data, gross and histologic findings, immunoperoxidase, flow cytometry, cytogenetics, and molecular testing Definitive diagnosis may not be possible on autopsy material Refer to appropriate references and consider consultation with hematopathologist Classic gross appearance of lymphoma: Enlarged nodes with tan-white, homogeneous, "fish flesh" cut surface Non-Hodgkin lymphoma Has extranodal forms (MALT lymphoma), nodal form, and splenic form B cell: Selected diagnoses Diffuse large cell lymphoma: Most common B-cell lymphoma; usually rapidly growing nodes Chronic lymphocytic lymphoma/small lymphocytic lymphoma: Early on, lymphocytosis; later on, lymphadenopathy, splenomegaly, anemia Hairy cell leukemia: Potentially massive splenomegaly, marrow involvement with cytopenias, abdominal but not peripheral adenopathy Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia): IgM spike; 30-40% splenomegaly and lymphadenopathy Follicular lymphoma: Nodes may have a grossly nodular cut surface Mantle cell lymphoma: Often adenopathy, splenomegaly, and bone marrow involvement; may involve GI tract (lymphomatous polyposis coli); may have fever, weight loss Burkitt lymphoma: Fastest growing tumor known T cell: Selected diagnoses Adult T-cell leukemia/lymphoma: Visceral involvement, skin lesions, osteolytic bone lesions, hypercalcemia Enteropathy associated T-cell lymphoma: GI lymphoma; arises in background of celiac disease; can present as weight loss and diarrhea or obstruction/perforation Mycosis fungoides/Sezary syndrome: Cutaneous lymphoma; variety of skin lesions; erythematous rash, plaques with adenopathy, mass lesions, erythroderma, circulating Sezary cells Angioimmunoblastic T-cell lymphoma: Fever and generalized adenopathy early on; later, hepatosplenomegaly and hemolytic anemia

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MACROSCOPIC FINDINGS

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht Lymph Nodes, Nonneoplastic Conditions External Examination

Body habitus: Weight loss associated with a variety of hematologic conditions

Skin

Pallor associated with anemia Rashes associated with cutaneous lymphomas Petechiae associated with thrombocytopenia Oral cavity: Gingival hyperplasia in acute monocytic leukemia

Lymphadenitis

Typically confined to single nodal group draining a lesion Some etiologic agents associated with grossly necrotizing inflammation Tuberculosis: Caseating lung focus + draining bronchial nodes = Ghon complex Cat scratch disease Infectious agents EBV: Adenopathy (particularly cervical), splenomegaly, fever Granulomas: Tuberculosis, some fungi, Brucella All are dangerous respiratory pathogens All pose substantial risk to autopsy personnel, use N95 particulate respirator Geographic necrosis: Cat scratch (Bartonella) Chronic reactive changes Preserved nodal architecture, patent sinuses Follicular hyperplasia with prominent germinal centers and tingible body macrophages Lots of variability in size and shape of lymphoid follicles Sarcoidosis Epithelioid granulomas (typically without necrosis)

s r s r e e k ook o o b eeb

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp 29

Autopsy Fundamentals: Autopsy Performance

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t Bone Marrow hht hht

Anaplastic large cell lymphoma: Adenopathy and extranodal involvement with weight loss and fever Hodgkin lymphoma Classic Hodgkin lymphoma: Some subtypes have characteristic gross findings Nodular sclerosis: Thickened fibrotic capsule and radiating bands of fibrosis; grossly nodular cut surface; typically mediastinal Mixed cellularity: Often involves abdominal nodes and spleen Metastasis Microscopic metastases often found in subcapsular sinuses first Diffuse replacement by metastasis and extracapsular extension can lead to matted lymph nodes

Splenic atrophy and autosplenectomy associated with sickle cell anemia Splenomegaly may occur early in course of disease Increases risk for infections especially with encapsulated bacteria Splenic lacerations Often associated with fractures of left lower ribs Can be seen associated with EBV (mononucleosis)

Multiple myeloma

Pallor secondary to anemia Findings related to thrombocytopenia: Ecchymoses and purpura Plasmacytomas: Soft tissue masses composed of plasma cells; can occur anywhere Lytic bone lesions and pathologic bone fractures, particularly axial skeleton Paraprotein-related renal disease: Myeloma cast nephropathy, amyloidosis, light chain deposition disease, consider immunofluorescence and ultrastructural studies on renal tissue Changes secondary to amyloidosis: Skin and shoulder joint nodules, macroglossia, peripalpebral purpura ("raccoon eyes") Leukemia Marrow: Often no gross abnormalities; histologic evaluation is essential Visibly thickened buffy coat layer in tubes of peripheral blood Pallor from anemia Ecchymoses and purpura from thrombocytopenia Infectious complications secondary neutropenia Metastasis: Often thoracolumbar 3rd most common site of epithelial metastasis (after lungs and liver) 73% of patients dying of breast cancer and 68% dying of prostate cancer have bony metastases Lung, thyroid, and renal tumors also frequently metastasize to bone

s r s r e e k k o o o o eebb Spleen

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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rrss e e k k o o o o o o b b b b e e / / e e / / e e GALT e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

Splenic Infarction

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Wedge-shaped pale areas with base at capsular surface Multiple infarcts suggest embolic cause Look for other evidence of bacterial endocarditis Valve vegetations, embolic infarcts in kidneys, brain Splenomegaly Portal hypertension: May be associated with cirrhosis, ascites, esophageal varices Hematolymphoid disorders Splenic marginal zone lymphoma: Splenomegaly, adenopathy confined to splenic hilum; bone marrow involvement; circulating villous lymphocytes Myeloproliferative disorders: Potentially massive splenomegaly, marrow abnormalities, teardrop red cells Hodgkin lymphoma Thalassemia major: Potentially massive splenomegaly from massive extramedullary hematopoiesis (EMH) Skull and other bone deformities: Result of massive chronic EMH Skin ulcerations Hepatomegaly Bilirubin gallstones Changes 2 to transfusion-related iron overload Amyloidosis: Firm, abnormally pale, waxy cut surfaces Follicular deposition of amyloid: Sago spleen Diffuse deposition of amyloid: Lardaceous spleen Other organs may be involved Storage diseases Gaucher disease: Diffusely fine granular cut surface Glycogen storage disorders Infectious diseases Visceral leishmaniasis (kala-azar) Schistosomiasis when associated with portal hypertension Rheumatologic conditions Felty syndrome: Rheumatoid arthritis, splenomegaly, neutropenia

Thymus

Thymoma

May be associated with myasthenia gravis Tan-pink cut surface; cystic changes common Thymic hyperplasia: Enlargement of thymus due to lymphoid infiltration (lymphoid hyperplasia, enlargement without inflammatory infiltration: True thymic hyperplasia) Lymphoid hyperplasia has increased numbers of germinal centers and is most frequently associated with myasthenia gravis but may be seen in other autoimmune diseases True thymic hyperplasia has normal-appearing thymus histologically: May be associated with endocrine abnormalities (Graves disease), sarcoidosis, and Beckwith Wiedemann syndrome or can be rebound after stress such as steroid therapy or chemotherapy

Hyperplastic Peyer patches

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Autopsy Fundamentals: Autopsy Performance

HEMATOPOIETIC SYSTEM

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m Thymus t t / / / / / / : : / / ss: ss: p p t t p p t t t t hhtFINDINGS hht MICROSCOPIC Peripheral Blood Chronic myelogenous leukemia (CML): Increase in immature red and white cell precursors, splenomegaly, Philadelphia chromosome Agnogenic myeloid metaplasia: Marrow fibrosis, teardrop red cells

Seen with variety of infections; classically described with Salmonella typhi In infants and young children, can serve as lead point for intussusception Extranodal marginal zone lymphoma (MALToma) Fleshy mass lesion May perforate or cause obstruction Most commonly gastric

Thymoma: Biphasic tumor composed of epithelial

Lymph Nodes

Red cell abnormalities

cells (plump or spindle shaped) and nonneoplastic lymphocytes

Sickle cell anemia: Sickle-shaped red cells, commonly in areas of low oxygen tension Thalassemia major: Target cells Parasites Malaria: Intraerythrocytic ring-shaped trophozoites; extracellular forms Babesia: Intraerythrocytic ring trophozoites Trypanosomes: Trypanosoma cruzi, Trypanosoma brucei Worms: Brugia malayi, Wuchereria bancrofti, Loa loa White cell abnormalities Leukemia: Circulating immature forms Acute leukemias: Decreased mature forms and circulating blasts CML: Erythroid and white cell precursors of every stage of maturity ("circulating marrow") Sezary syndrome: Circulating medium to large T cells with cerebriform nuclei

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s r s r e e k ook o o o o b b b b e e / / e e / SELECTED REFERENCES / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Non-Hodgkin lymphoma: General comments

In most cases, normal nodal architecture completely effaced by infiltrate of malignant lymphocytes Loss of subcapsular sinuses and germinal centers Hodgkin lymphoma: General comments Diagnosis rests on identification of Reed-Sternberg (RS) cells and variants Classic RS cell: Large, atypical cell, binucleated with prominent ("owl eyes") nucleoli; positive with immunoperoxidase for CD15 and CD30 RS cells are rare (a few percent); background of benign mixed inflammatory cells Subtypes Nodular sclerosing: RS and lacunar cells on inflammatory background; node divided by fibrotic bands (60-80% of cases) Mixed cellularity: Diffuse mixed inflammatory infiltrate and classic RS cells (15-30%) Lymphocyte-rich: RS or lacunar cells on predominantly lymphocytic background (5%) Lymphocyte-depleted: Scant background, many RS cells and bizarre variants readily identifiable (< 1%) Nodular lymphocyte-predominant: Rare or absent RS cells; lymphocytic and histiocytic cells CD20(+), CD15(-), CD30(-)

Marrow

2. 3.

Podduturi V et al: A case series of clinically undiagnosed hematopoietic neoplasms discovered at autopsy. Am J Clin Pathol. 143(6):854-60, 2015 Podduturi V et al: Sickle cell trait as a contributory cause of death in natural disease. J Forensic Sci. 60(3):807-11, 2015 Al-Salem AH: Splenic complications of sickle cell anemia and the role of splenectomy. ISRN Hematol. 2011:864257, 2011 Sens MA et al: Unexpected neoplasia in autopsies: potential implications for tissue and organ safety. Arch Pathol Lab Med. 133(12):1923-31, 2009 Coleman RE: Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 12(20 Pt 2):6243s-6249s, 2006

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Leukemia

Acute leukemias: Requires > 20% blasts in marrow aspirate Blasts are CD34(+) Acute myelogenous leukemia Decreased/absent mature granulocytes Myeloblasts: Cytoplasmic granules, Auer rods; CD33(+), CD13(+) Acute lymphoblastic lymphoma Blasts usually lack granules Lymphoblasts: TdT(+), pax-5(+), CD22(+) Multiple myeloma > 30% plasma cells in bone marrow aspirate; CD138(+) Immature/atypical plasma cells often present May be accompanied by paraprotein in blood/urine Myeloproliferative disorders Polycythemia vera: erythroid precursors, hematocrit, splenomegaly, JAK2 mutation Essential thrombocytosis: megakaryocytes, platelet count

Autopsy Fundamentals: Autopsy Performance

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s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Gross and Microscopic Features

(Left) This image shows the cut surface of a thymoma taken from a patient with myasthenia gravis. The thymus is not typically grossly visible in adults, but remnants may be found in the adipose tissue in anterior mediastinum. (Right) Many conditions can cause splenomegaly. The differential diagnosis for massive splenomegaly is more limited. Massive splenomegaly (spleen tip in LLQ or pelvis or across midline) is most often seen in myeloproliferative disorders, certain lymphomas, thalassemia major, Gaucher disease, and kala-azar.

(Left) This cluster of enlarged, matted, lymph nodes was found in a patient with a highgrade B-cell lymphoma. Note the tan-pink, homogeneous, "fish flesh" appearance. (Right) This section of a lymph node with follicular lymphoma shows replacement of the normal nodal architecture by follicles that lack the germinal centers and tingible macrophages seen in benign follicular hyperplasia.

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(Left) Lymph nodes involved in sarcoidosis typically show diffuse involvement by epithelioid granulomas without central necrosis, although necrosis can occasionally be seen. (Right) Classic Hodgkin lymphoma is most typically characterized by large, atypical, binucleate Reed-Sternberg cells with prominent eosinophilic nucleoli (and variants thereof) on a background of benign mixed inflammatory cells.

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HEMATOPOIETIC SYSTEM

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(Left) Acute leukemia is typically characterized by a hypercellular bone marrow (note the near complete lack of fat), decrease or absence of mature forms, and increase in blasts. (Right) This high-power field shows monotonous blast cells with a remarkably increased nucleus:cytoplasm ratio (just a thin rim of cytoplasm is visible) and "cookie cutter" nucleoli. Note that no mature leukocytes are visible. A definitive distinction between AML and ALL often requires special testing.

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) This marrow was taken from a patient with agnogenic myeloid metaplasia (a.k.a. myelofibrosis). Note the marrow fibrosis. Most patients also have splenomegaly, sometimes massive splenomegaly. (Right) This Wright-Giemsastained smear of peripheral blood from a patient with agnogenic myeloid metaplasia shows a teardropshaped red cell . Teardrop cells (or dacrocytes) can also be seen in other disorders that replace the marrow.

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

(Left) This section of bone marrow from a patient who died with multiple myeloma shows near complete replacement of normal marrow elements by plasma cells including a binucleate plasma cell . (Right) This Wright-stained peripheral blood smear shows an intraerythrocytic ring-shaped trophozoite . In the absence of extracellular parasitic forms, it may be hard to distinguish between Babesia and malaria. Travel history is essential.

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt GASTROINTESTINAL SYSTEM

rrss e e k k o o o o eebb

s r s r e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht TERMINOLOGY Colonic dilatation > 12 cm that is not caused by mechanical obstruction is often referred to as megacolon. The abdomen is typically distended and tympanitic.

Aortoesophageal fistula (demonstrated with the probe) is a rare, often fatal cause of upper gastrointestinal hemorrhage. It usually arises in the setting of aortic pathology such as an aortic aneurysm.

Free colon from its mesenteries and attachments to

Definitions

Upper gastrointestinal (GI) tract: From lips to ligament

s r s r e e k ook o o b eeb

body wall Use scissors, scalpel, or blunt dissection Expect resistance at cecum and gastrocolic ligament Place 2 ties around distal sigmoid colon and transect between them Open intestines using an enterotome (scissors with a blunt leading blade) Insert blunt end into bowel lumen; do not snip Hold enterotome open (~ 45) and pull antimesenteric side downward onto hinge

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : Dissection of Upper GI Tract ss ss p p t t p p t t t t DISSECTIONh OF hht ht GASTROINTESTINAL TRACT

of Treitz Esophagus, stomach, duodenum, pancreas, extrahepatic biliary tree Lower gastrointestinal tract: From ligament of Treitz to anus Jejunum, ileum, ascending colon, transverse colon, descending colon, sigmoid colon, rectum

Use scissors or scalpel to free gallbladder from hepatic bed

Cut hepatic duct, portal vessels, inferior and superior vena cava

Handling of Gastrointestinal Tract

Remove liver from upper GI tract Free esophagus from laryngopharynx, posterior

Rinse in cold water Do not rub mucosae Fix thoroughly; autolysis occurs soon after death

Leaving biliary tract and pancreas attached to

s s r r s s r r e e e e k k ook ook o o oo o o b b b b b eeb Dissection of Lower GI Tract e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p Dissection of Biliary Tree t t hhtt hhtt If taking cultures, do so before manipulating GI tract Open, rinse, and examine entire GI tract

Retract greater omentum and transverse colon upward and displace small bowel to right Ligament of Treitz is visible where small bowel emerges from retroperitoneum Place 2 ties around proximal jejunum and transect jejunum between them Free jejunum and rest of small bowel from mesentery 1st alternative Hold cut end of jejunum in nondominant hand to apply traction Use scalpel with a violin bow motion to cut mesentery near its attachment to bowel 2nd alternative Use scissors to cut through mesentery near its attachment to small bowel

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trachea, and aorta

duodenum, free stomach and duodenum from aorta

Open esophagus along posterior midline Continue cut along greater curvature of stomach Continue cut to open duodenum, taking care to preserve ampulla of Vater

Gently squeeze gallbladder and look for appearance of bile at ampulla of Vater

Probe common bile duct into ampulla of Vater Open gallbladder, hepatic duct, and common bile duct

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht Dissection of Pancreas 1st alternative

Transect tail of pancreas to identify pancreatic duct Insert a fine probe into pancreatic duct Use probe as a guide and bisect pancreas lengthwise along duct

: s s p t p t hhtt

rrss e e k k o o o o eebb

Autopsy Fundamentals: Autopsy Performance

GASTROINTESTINAL SYSTEM

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t Special Procedures hht hht Leave half of pancreas with exposed duct attached to duodenum Probe proximal pancreatic duct into ampulla of Vater 2nd alternative Serially cross section tail and body of pancreas Probe proximal pancreatic duct into ampulla of Vater

Eversion of esophagus (to identify esophageal varices)

Use a forceps to thread a string down proximal end of unopened esophagus and into stomach Tie opposite end around proximal end of esophagus Open stomach along greater curvature Grasp free end of string and pull to evert esophagus Inflation of gastrointestinal segment Clamp one end of specimen closed Rinse with cold water to remove contents Fill specimen with formalin and clamp open end Fix overnight Use scissors to open fixed specimen

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Note presence, characteristics (fibrinous, fibrous,

dense, fine) of adhesions Note presence, characteristics (location, contents, incarceration) of any hernias Endometriosis Serosal-based implants/lesions with variable appearance Red, bluish, powder burn black, white and fibrous May cause fibrosis and kinking of involved bowel segments

Esophagus Structural

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t Sections for Microscopy hht hht Sample any grossly abnormal tissues Sections of grossly normal tissue will vary according to local practice

s r s r e e k ook o o b eeb

Zenker diverticulum: Outpocketing of posterior pharyngeal wall just above esophagus Mallory-Weiss tears: Linear, longitudinal tears in mucosa, usually distal Rupture (Boerhaave syndrome): Usually in left lower esophagus Infectious: More common in immunosuppressed patients Candida: White plaques Herpes: Blisters early on, followed by ulcers CMV: Single or multiple ulcers, especially in distal esophagus Inflammatory Reflux esophagitis: Most common cause of symptomatic esophagitis Erythema in distal esophagus ulceration Barrett esophagus Velvety tan-red mucosa in distal esophagus/GEJ Eosinophilic esophagitis "Corrugated" esophagus with concentric mucosal rings Chemical esophagitis Neoplastic Squamous cell carcinoma Adenocarcinoma Typically in distal esophagus May arise in setting of Barrett esophagus with dysplasia Miscellaneous Esophageal varices Dilated esophageal submucosal veins in patients with portal hypertension May see associated cirrhosis, ascites, splenomegaly May collapse postmortem; consider everting esophagus to demonstrate them Acute esophageal necrosis ("black esophagus") Friable black distal mucosa; stops abruptly at GE junction Aortoesophageal fistula

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . MACROSCOPIC FINDINGS / / t t / / / / : : / / : : ss ss p p External Examination t t p p t t t t hht hht Suggested sections of normal tissue

Section of gastroesophageal junction Section of small bowel Section of colon Section of pancreas

Body habitus Cachexia

Mouth, nose, anus

Evidence of frank blood, melena, "coffee ground" emesis Skin Surgical scars Pallor of skin, possibly due to mucous membranes, could indicate anemia and GI hemorrhage Jaundice Association with portal hypertension, cirrhosis, ascites Risk of GI hemorrhage Consider everting esophagus to demonstrate varices Umbilical (Sister Mary Joseph) nodule 50% associated with GI malignancy Ostomies: GI diversion Taut abdominal distension Peritonitis, ruptured viscus, toxic megacolon

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt Stomach

rrss rrss e e e e k k k k o o In Situ Examination of Organs o o o o o o o o b b b b eebb e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp Inspect any anastomoses (especially recent) If evidence of peritonitis, attempt to locate source Intraluminal blood is often visible through walls of bowel

Infectious/inflammatory

Acute gastritis Associated with aspirin, ethanol, smoking, shock, chemical irritation Hyperemia erosions, hemorrhages Chronic gastritis Associations: Ethanol, smoking, Helicobacter pylori, pernicious anemia

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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Mucosal hyperemia and mucosal flattening Peptic ulcer disease Sharply punched-out gastric or duodenal ulcers without raised edges May be associated with H. pylori Multiple ulcers &/or ulcers in unusual locations should suggest Zollinger-Ellison syndrome Stress ulcers Typical lesions: Punctate, scattered areas of dark red discoloration and mucosal hemorrhage Seen in patients with severe acute illnesses: Trauma, burns, sepsis, shock, increased intracranial pressure Wischnewski ulcers Multiple submucosal hemorrhages ("leopard spots") Associated with hypothermia Hypertrophic gastropathy: Giant cerebriform rugal folds Menetrier disease Excessive mucus production, protein loss, decreased acid Gastric gland hyperplasia secondary to ZollingerEllison syndrome Gastrin producing pancreatic tumor increased acid production Increased acid, associated with multiple refractory peptic ulcers Almost 25% of patients with multiple gastrinomas will have multiple endocrine neoplasia type I; examine pituitary and parathyroids Hypertrophic-hypersecretory gastropathy Hyperplasia of parietal and chief cells Increased acid, associated with multiple refractory peptic ulcers Neoplastic Gastric polyps Fundic gland polyps Hyperplastic polyps Adenocarcinoma Intestinal type: Raised, sometimes ulcerated masses Diffuse type (a.k.a. signet ring cell type, leather bottle stomach, linitis plastica): Diffuse infiltration of gastric wall without obvious mass Lymphoma: Usually extranodal marginal B-cell lymphoma Homogeneous, tan-white, "fish flesh" cut surface May be associated with chronic H. pylori infection Gastrointestinal stromal tumor (GIST): Typically exophytic subserosal masses Miscellaneous Bezoar: Mass of undigested material Vegetable material (most common), hair, medications, etc.

May contain heterotopic gastric or pancreatic tissue Volvulus Twisting of bowel along its mesentery Dilation and hyperemia proximal to obstruction Infectious/inflammatory Celiac disease Flattening of mucosal villi; increased intraepithelial lymphocytes May be associated with weight loss and diarrhea Laboratory testing: Antigliadin and anti-tissue transglutaminase antibodies, HLADQ2 and DQ8 Inflammatory bowel disease (IBD) Chronic active inflammatory process Ulcerative colitis: Involves rectum and can extend proximally; no skip areas; inflammation confined to mucosa and submucosa, does not involve upper GI Crohn disease: Usually focused in lower GI, but can involve any portion of GI tract; can show skip areas, transmural inflammation with wall thickening Ischemia Affected segment: Dusky, dark red-purple, congested; may progress to black color and necrosis Examine mesenteric vessels Neoplastic Neuroendocrine (carcinoid) tumors: Most common primary tumor of small bowel If metastatic to liver, may be associated with carcinoid syndrome Adenocarcinoma: Much less common than colonic adenocarcinoma GIST Lymphoma Usually extranodal marginal zone B-cell lymphoma T-cell lymphomas may arise in setting of celiac disease

Colon and Rectum

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Structural/mechanical

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Hernias Meckel diverticulum: Vitelline duct remnant 2-3 feet proximal to cecum

Structural

Diverticular disease At mesenteric border, near point of penetration of small vessels May be associated with abscess formation and fistula formation Volvulus: Can lead to ischemia and necrosis Sigmoid is most common location, especially older patients; associated with constipation Cecum 2nd most common location Infectious/inflammatory Bacterial, viral infections Antibiotic-associated (Clostridium difficile) colitis Characteristic adherent yellow plaques (pseudomembranes) IBD Ulcerative colitis and Crohn disease Crohn disease may be associated with fistula formation, sinus tracts Ischemia

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GASTROINTESTINAL SYSTEM

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

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s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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s r s r e e k ook o o o o b b b b e e / / e e / SELECTED REFERENCES / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Affected segments dusky dark red-purple; can progress to black and necrotic May be result of low flow or vascular occlusion (e.g., by thromboemboli) Watershed areas (splenic flexure and rectosigmoid junction) are particularly vulnerable Neoplastic Hyperplastic and serrated polyps Juvenile polyps Neuroendocrine tumors (carcinoid tumors) Submucosal, yellowish mass Especially common in rectum and tip of appendix Adenomas Tubular, villous, tubulovillous 30% of adults at autopsy risk of carcinoma if numerous polyps, family history, > 1 cm size Leiomyomas GIST Adenocarcinoma 98% of colonic malignancies Neuroendocrine (carcinoid) tumors Miscellaneous Megacolon Diameter > 12 cm (varies) Congenital or acquired Stercoral ulcers Abrasions from hard stool Commonly seen in debilitated patients

Inflammation/infection

Appendicitis Idiopathic Obstructive: Fecalith, tumor, lymphoid hyperplasia, Enterobius vermicularis Yersinia enterocolitica: granulomatous appendicitis IBD Neoplasms Adenoma Adenocarcinoma Mucinous adenocarcinoma May be associated with pseudomyxoma peritonei Neuroendocrine tumors (carcinoids)

Intestinal type: Infiltrating malignant glands Diffuse type: Infiltrate of signet ring cells without obvious mass Signet ring cells may be mistaken for inflammatory cells Tumor cells will stain for keratin and intracytoplasmic mucin Will be negative for E-cadherin Neuroendocrine (carcinoid) tumor Cords and trabeculae of monotonous cells Nuclei with fine chromatin GIST Arise from interstitial cells of Cajal in intramuscular neural plexus May be spindle celled or epithelioid Inflammatory bowel disease Features common to ulcerative colitis and Crohn disease Acute changes: Neutrophils, cryptitis, crypt abscess Chronic changes: Regenerative changes with branched crypts, lymphocytes in lamina propria Ulcerative colitis Typically limited to mucosa; no thickening of bowel wall No granulomas Crohn disease May involve full thickness of bowel wall May be associated with sinus and fistula formation Granulomas may be seen

Epelboym I et al: Zollinger-Ellison syndrome: classical considerations and current controversies. Oncologist. 19(1):44-50, 2014 Ishida M et al: Intravascular gas distribution in the upper abdomen of non-traumatic in-hospital death cases on postmortem computed tomography. Leg Med (Tokyo). 13(4):174-9, 2011 Finkbeiner WE et al. Autopsy Pathology: A Manual and Atlas. Philadelphia: Saunders/Elsevier, 2009 Rose AG.Atlas of gross Pathology with Histologic Correlation. New York: Cambridge University Press, 2008 Ludwig J. Current Methods of Autopsy Practice. 2nd ed. Philadelphia: W.B. Saunders, 1979

s s r r s s r r e e e e k k ook ook o o oo o o b b b b b eeb MICROSCOPIC FINDINGS ee/e e / e e / / e e m m .t.Findings .t.m m t t / / / / Some Characteristic Microscopic / / : : / / : : s s s s p p t t p p t t hhtt hhtt 3. 4. 5.

Eosinophilic esophagitis

Eosinophilic infiltrate, often patchy, with foci showing > 15 eosinophils per high-power field Epithelial hyperplasia Reflux esophagitis Elongated epithelial pegs and mild eosinophilic infiltrate Barrett esophagus Intestinal metaplasia of gastric mucosa at gastroesophageal junction Dysplasia in Barrett associated with risk of adenocarcinoma Gastric adenocarcinoma

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Autopsy Fundamentals: Autopsy Performance

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: s s p t p t hhtt GASTROINTESTINAL SYSTEM

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Removal of Gastrointestinal Tract

(Left) The ligament of Treitz separates the distal duodenum from the jejunum. It can be located by lifting the transverse colon with the attached gastrocolic ligament and pushing the small bowel (previously removed in this diagram) to the right. The proximal jejunum can be seen emerging from the retroperitoneum to the left of the midline. (Right) The congested jejunum can be seen emerging from the retroperitoneum below the transverse colon .

(Left) To remove the small bowel, the free end is held in the nondominant hand and traction is applied to render the attachment to the mesentery taut. A scalpel is used in a violin bow motion to progressively free the small bowel near its attachment to the mesentery. (Right) The colon can be freed from its attachments to its mesenteries and the body wall by using a scalpel (shown), scissors, or by blunt dissection.

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

(Left) Here the duodenum is being freed from its vascular attachments. The cut end of the superior mesenteric artery can be seen. (Right) Meckel diverticulum is shown , a remnant of the embryonic vitelline duct. It typically arises 2-3 feet from the cecum and may contain ectopic gastric or pancreatic tissue.

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GASTROINTESTINAL SYSTEM

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s r s r e e k k o o o o eebb

(Left) Zenker diverticulum is an outpocketing of the mucosa and submucosa of the pharynx that arises immediately above the upper esophageal sphincter. (Right) The mucosal surface of this stomach shows the thickened, cerebriform mucosal folds that characterize hypertrophic gastropathy. This was a case of hypertrophichypersecretory gastropathy, Menetrier syndrome, and Zollinger syndrome may appear similar.

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) The gastric mucosa is diffusely and strikingly hyperemic in this case of acute gastritis. Causes include aspirin, ethanol, shock, and chemical irritants. (Right) This close-up image of the gastric mucosa from a patient who died of hypothermia shows diffuse, punctate, submucosal hemorrhages in a leopard spot pattern. Known as Wischnewski ulcers, these lesions, though present in 40-90% of cases of hypothermia, are not specific for any single etiology.

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

(Left) Intestinal-type gastric adenocarcinoma characteristically presents as a mass that rises above the surrounding gastric mucosa. Central ulceration is common. For unknown reasons, there has been a marked decrease in the worldwide incidence of gastric cancer. (Right) Shown here is a section of gastric wall from a patient with diffuse (signet ring cell) -type gastric adenocarcinoma. Contrast the involved wall with the adjacent normal wall .

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt GASTROINTESTINAL SYSTEM

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Small Bowel

(Left) This whole-mount image of a section of small bowel involved with lymphoma shows a transmural infiltrate that replaces the full thickness of the bowel wall. This patient presented with an acute abdomen and perforated jejunum. (Right) A higher power view of the small bowel shows effacement of normal structures by a diffuse infiltrate of lymphocytes. Most GI lymphomas are extranodal marginal zone Bcell lymphomas or diffuse B-cell lymphomas. T-cell lymphoma is unusual.

(Left) This close-up image of bowel mucosa shows a slightly raised submucosal nodule . The appearance is typical of a neuroendocrine tumor or carcinoid tumor. The cut surface of such tumors is often yellow. (Right) This H&E section of a neuroendocrine tumor shows islands and trabeculae of monotonous cells with fine nuclear chromatin. Immunoperoxidase stains for synaptophysin and chromogranin were positive.

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebbI

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

(Left) This image is an example of GI involvement by endometriosis. The arrow indicates a fibrous mass that involves the serosa and muscularis of this segment of small bowel. The overlying mucosa is unremarkable. Lesions like this may be mistaken for primary or metastatic malignancies. (Right) This H&E-stained section shows endometriosis involving the muscularis of the small bowel. Benign endometrial glands and stroma can be seen.

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GASTROINTESTINAL SYSTEM

rrss Colon e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

(Left) This close-up image of a colonic adenocarcinoma shows a polypoid tumor rising above the surrounding uninvolved mucosa. The cut surface shows the tanwhite tumor infiltrating into the muscularis propria. (Right) Typical colonic adenocarcinoma is composed of malignant glands with cribriformed architecture made up of markedly dysplastic cells. There is loss of normal nuclear polarity and mucin production. Areas of "dirty" necrosis are particularly characteristic.

(Left) Loops of black, dusky, ischemic small bowel are indicated . Contrast the appearance of the adjacent tan-pink, normal small bowel with smooth glistening serosal surfaces. (Right) Volvulus is the result of a segment of bowel twisting on its mesentery. This congested segment of sigmoid colon shows a normal-diameter portion nearer the twist, and a dilated distal portion more distally. The sigmoid colon is the most commonly involved segment of the GI tract.

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

(Left) Antibiotic-associated colitis results from selective overgrowth of toxinproducing strains of Clostridium difficile following antibiotic therapy. The mucosal surface shows hyperemia and tanyellow plaques or pseudomembranes. (Right) The mucosal surface of this segment of colon involved by inflammatory bowel disease shows pseudopolyp formation and a characteristic cobblestone appearance.

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt HEPATOBILIARY SYSTEM

rrss e e k k o o o o eebb

s r s r e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht TERMINOLOGY This cirrhotic liver has a pale yellow appearance due to fatty liver disease. The falciform ligament separates right and left lobes. The coronary ligament attaches to the diaphragm.

Definitions

Includes liver, extrahepatic bile ducts, gallbladder, and

The gallbladder mucosa is normally green-brown. Scattered yellow specks represent cholesterolosis. Few small yellow cholesterol stones are also present.

Right and left hepatic ducts join to form common hepatic duct in liver hilum; common hepatic duct joins cystic duct from gallbladder to form common bile duct (CBD) CBD is most anterior structure in porta hepatis; portal vein lies posteriorly and to left of CBD; hepatic artery and nerves lie most posteriorly CBD passes posterior to 1st portion of duodenum into head of pancreas In situ evaluation of continuity of ductal system: Open 1st and 2nd portions of duodenum to expose ampulla, squeeze gallbladder to express bile through extrahepatic ducts and out of ampulla Gallbladder Hollow sac inferior to right lobe of liver Remove with liver by transecting CBD or free it from liver bed and open in continuity with ductal system Exocrine pancreas Identify pancreas in retroperitoneum posterior to stomach extending between duodenum and spleen Main pancreatic duct runs length of organ and drains into ampulla accessory duct, which drains into minor papilla Intrapancreatic portion of CBD runs inferiorly through pancreatic head and empties into ampulla (usually joins main pancreatic duct proximal to ampulla) Can keep in continuity with extrahepatic bile ducts (if ductal pathology is suspected) or separate from duodenum and spleen

s s r r s s r r e e e e k k k ooMACROSCOPIC ook FINDINGS o o o o o o b b b b b eeb External Examination e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht exocrine pancreas

Findings suggesting hepatobiliary disease

Jaundice (indicates bilirubin of at least 2.5-3 mg, seen with many hepatobiliary diseases) Ascites (chronic/acute liver disease, malignancy, pancreatitis) Muscle wasting/cachexia (malnutrition: Chronic liver failure, chronic pancreatitis, malignancy) Palpable periumbilical lymph node (metastatic pancreatic carcinoma) Periumbilical edema/hematoma (Cullen sign: Hemorrhagic pancreatitis) Flank bruising (Grey Turner sign, indicates intra-/retroperitoneal hematoma: Hemorrhagic pancreatitis)

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / General Features / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt Liver

Located mainly in right upper quadrant beneath 7th-11th ribs, inferior to diaphragm Same dissection for either Rokitansky or Virchow methods Open portal vein, vena cava, and hepatic veins into hilum Hepatic arteries can be opened or examined by transverse sectioning Remove liver by freeing attachments to diaphragm, falciform and coronary ligaments, stomach, and duodenum Extrahepatic bile ducts

rrss e e k k o o o o eebbI 2 42

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht Specimen Handling Liver

Dissect from diaphragmatic attachments, serially section in horizontal plane at 1 cm intervals Normal parenchyma red-brown, normal weight 1,400-1,600 g

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: s s p t p t hhtt Autopsy Fundamentals: Autopsy Performance

HEPATOBILIARY SYSTEM

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Sample right/left lobes, hilum, any gross pathology

Extrahepatic bile ducts

Cannulate CBD and open retrograde into pancreas Note presence of stones and lesions, section any gross pathology Gallbladder Open CBD into cystic duct or open gallbladder from fundus if cystic duct is too small Normal size 7-10 cm, wall thickness 1-3 mm Record quantity and quality of bile and presence, color, and shape of stones Normal mucosa is green and velvety Mucosa autolyzes quickly due to bile (sample early in autopsy procedure if pathology suspected) Representative sections of entire thickness of gallbladder wall and any gross pathology Exocrine pancreas Normal size and weight 15 cm, 60-140 g Best dissection method to probe CBD and pancreatic duct from ampulla and bisect organ along that plane May serially section if difficult to probe If cystic lesion is present, note relationship to ductal system Section head and tail of pancreas and any gross pathology

s r s r e e k ookGeneral Features o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht CLINICAL CORRELATES

MICROSCOPIC FINDINGS

Liver

Polygonal hepatocytes with eosinophilic, sometimes granular cytoplasm and well-defined borders with prominent nucleolus, arranged in cords 1, sometimes 2 cells thick variation in size, number of nuclei, and lipofuscin pigment deposition with age Plates/cords separated by sinusoids lined by specialized endothelial cells (negative for CD31 and CD34) Kupffer cells (specialized hepatic macrophages) and occasional lymphocytes lie in sinusoids Space of Disse located between sinusoids and hepatocytes Contains hepatic stellate cells (involved in fibrogenesis) and extracellular matrix including reticulin network Parenchyma divided into 3 zones with decreasing tissue oxygenation Zone 1 (periportal), zone 2 (midzonal), and zone 3 (centrilobular/perivenular) Portal tracts contain interlobular bile duct, portal venule, hepatic arteriole, lymphatics and occasional lymphocytes embedded in fibrous stroma collagen density and number of mononuclear inflammatory cells with age Interlobular bile ducts lined by cuboidal or low columnar epithelium ([+] for CK7 and CK19), which drain into larger septal ducts lined by tall columnar epithelium

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Bile canaliculi located between hepatocytes, not seen on H&E stain, highlighted by polyclonal carcinoembryonic antigen (CEA) Bile flow: Hepatocytes bile canaliculi canals of Hering bile ductules at periphery of portal tracts interlobular ducts septal ducts toward hilum; bile not seen on H&E stain in normal liver Extrahepatic bile ducts Lined by tall columnar cells with unevenly distributed peribiliary mucous glands, muscle layer present in distal 1/3 of ductal system Gallbladder Lined by simple columnar epithelium arranged in branching folds; no discrete muscularis mucosa or submucosa Muscularis propria and perimuscular connective tissue/adventitia, lined by peritoneum except where attached to liver Rokitansky-Aschoff sinuses: Outpouching of mucosa that penetrate muscle wall Ducts of Luschka: Lobular aggregates of ductules lined by cuboidal epithelium deep in wall adjacent to liver Exocrine pancreas Acini: 80% of parenchyma, basophilic/amphophilic pyramid-shaped to columnar cells with apical zymogen granules, oriented radially within acinus, scant stroma Centroacinar cells: Located in center of acinus, pale cytoplasm, single or in clusters Intercalated ducts (cuboidal epithelium) intralobular ducts (cuboidal epithelium) interlobular ducts (cuboidal-columnar epithelium) main pancreatic duct (simple columnar mucinous epithelium)

Pertinent Antemortem Labs

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhttFINDINGS FREQUENT AUTOPSY Hepatobiliary: Aspartate transaminase (AST), alanine

transaminase (ALT), alkaline phosphatase, bilirubin, gamma-glutamyl transferase (GGT) Liver: Viral hepatitis serologies, autoimmune markers (e.g., anti-smooth muscle and antimitochondrial antibodies), -fetoprotein, ceruloplasmin, -1antitrypsin (A1AT), iron studies Exocrine pancreas: Amylase, lipase

Liver

Shock changes

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp Gross: "Nutmeg" liver with variegated cut surface due to zone 3 hemorrhagic necrosis and preserved portal areas; larger areas of necrosis/infarction are pale and soft Microscopic: Centrilobular congestion hepatocellular coagulative necrosis, periportal areas usually preserved (except with massive necrosis/ infarction)

Autopsy Fundamentals: Autopsy Performance

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: s s p t p t hhtt HEPATOBILIARY SYSTEM

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Sepsis changes

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

Gross: Green discoloration of parenchyma (cholestasis), abscesses, ulcers/erosions thickening of bile ducts (cholangitis) Microscopic: Canalicular cholestasis, ductular cholestasis associated neutrophils, neutrophils within walls and lumina of bile ducts (acute cholangitis) Cirrhosis Gross: Nodules surrounded by fibrous tissue, micronodular ( 3 mm), macronodular, or mixed Microscopic: Regenerative nodules of hepatocytes surrounded by fibrous bands without central veins Tumors Benign: Hemangioma (most common primary tumor), focal nodular hyperplasia, hepatocellular adenoma, cysts, bile duct adenoma Malignant: Metastasis (most common), hepatocellular carcinoma, cholangiocarcinoma

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intrahepatic ducts Complications include ascending cholangitis abscesses, pancreatitis, ileus Cholangiocarcinoma, "Klatskin tumor" when present at confluence of right and left hepatic ducts

s r s r e e k ook o o b eeb

Gallbladder

Cholelithiasis

Gross: Edematous, pale, indurated parenchyma, fat necrosis (yellow nodules calcification), hemorrhage/necrosis, pseudocysts, abscesses Microscopic: Acute inflammation, edema, fibrinous exudate, hemorrhage and necrosis of all parenchymal components, fat necrosis, calcification Chronic pancreatitis Gross: Focal, segmental, or diffuse involvement by fibrosis, indurated mass-like, irregular ductal dilatation calculi, atrophy Microscopic: Irregular loss of acinar/ductal tissue, chronic inflammation/fibrosis with preservation of lobular architecture, duct ectasia inspissated secretions, ductal metaplasia, islets usually preserved Cystic neoplasms Communication with ductal system: Intraductal papillary mucinous neoplasm and variants No communication with ductal system: Serous cystadenoma (most common cystic neoplasm), mucinous cystic neoplasm, acinar cell cystadenoma Malignant tumors Adenocarcinoma (pancreatic duct, ampulla, or CBD), pancreatic endocrine neoplasm, solid pseudopapillary neoplasm, acinar cell carcinoma

s r s r e e k ANCILLARY TESTS k o o o o o o b b Serum b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Cholesterol: Pure or mixed with calcium, phosphate, or bile, yellow to green, smooth, hard and round to oval, sometimes popcorn-like Pigment: Unconjugated bilirubin and calcium salts, chronic hemolysis (black stones), and infection (brown stones) are risk factors; may be spiculated Cholesterolosis: Due to bile supersaturation with cholesterol, yellow specks on mucosa, foamy macrophages in lamina propria, cholesterol polyps Acute cholecystitis Gross: Enlarged, red-green-black discoloration, serosal fibrinopurulent exudate, thickened edematous wall, fibrinous/purulent contents, mucosal erythema/ulcers Microscopic: Acute inflammation, mural edema with myofibroblastic proliferation, congestion, ulcers, abscesses, gangrene Chronic cholecystitis Gross: May appear normal, serosal fibrosis, variably thickened wall, mucosa usually normal or ulcerated under impacted stones Microscopic: Mucosal chronic inflammation, thickened wall with Rokitansky-Aschoff sinuses, pyloric and intestinal metaplasia Adenomyoma (localized mass-like diverticulum) Gross: Polypoid nodule in wall of fundus with cystic cut surface, overlying mucosal dimple Microscopic: Mucosal herniation with cystically dilated glands lined by normal epithelium and prominent smooth muscle hypertrophy Tumors: Adenomas, cysts, adenocarcinoma

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Acute pancreatitis

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t . . / Extrahepatic Bile Ducts ://t t t / / / : / / : : ss ss p p t t p p t t t t hht hht Choledocholithiasis: Usually in CBD, may involve

Exocrine Pancreas

AST, ALT, amylase and lipase rapidly postmortem, not useful

GGT data varies, can possibly be used in evaluation of biliary disease postmortem

Bile slightly postmortem, accurate if markedly Antibodies for viral hepatitis B and C are reliable PCR for hepatitis B DNA and hepatitis C RNA are reliable

s r s r e e k ook o oo o b b b b SELECTED REFERENCES e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt Urine

Bile and urobilinogen not normally present in urine; detection postmortem is accurate

1. 2.

Palmiere C et al: Postmortem chemistry update part II. Int J Legal Med. 126(2):199-215, 2012 Weedn, VW et al: Postmortem Chemistry. In Sapse D et al: Forensic Science Advances and Their Application in the Judiciary System. Boca Raton: CRC Press. 235-54, 2011 Eriksen MB et al: Postmortem detection of hepatitis B, C, and human immunodeficiency virus genomes in blood samples from drug-related deaths in Denmark*. J Forensic Sci. 54(5):1085-8, 2009

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

: s s p t p t hhtt

: s s p t p t hhtt Autopsy Fundamentals: Autopsy Performance

HEPATOBILIARY SYSTEM

rrssand Excised Organs rrss In Situ e e e e k k k k o o o o o o o o o o b b b b eebb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

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(Left) The gallbladder empties bile via the cystic duct . The cystic duct joins the common hepatic duct as it exits the liver to form the common bile duct . This empties into the duodenum after traversing the pancreatic head and joining the main pancreatic duct at the ampulla . (Right) The extrahepatic bile duct system is opened to show the cystic duct joining the common hepatic duct as it exits the liver to form the common bile duct .

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) The head of the pancreas rests in the Cshaped 2nd and 3rd portion of the duodenum. The uncinate process extends medially from the head and posterior to the superior mesenteric vein and artery . The tail of the pancreas extends to the hilum of the spleen . The splenic artery lies superior to the pancreatic body. (Right) The pancreas is bisected along the pancreatic duct . The common bile duct traverses the pancreatic head (splenic artery ).

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

(Left) The portal vein is opened as it exits the liver to show a small thrombus . The gallbladder extends inferiorly from this cirrhotic liver. (Right) The caudate and quadrate lobes can be viewed from the posterior surface of the liver. The gallbladder is located to the right of the quadrate lobe and inferior to the porta hepatis , which contains the hepatic portal vein, hepatic artery, and common hepatic bile duct (right and left lobes).

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt HEPATOBILIARY SYSTEM

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Normal Histology

(Left) The liver parenchyma can be divided into 3 zones of hepatocytes: (1) Periportal , (2) mid zonal , and (3) perivenular/centrilobular . (Right) The portal tract is composed of an interlobular bile duct , hepatic arteriole , and portal venule embedded in a fibrous stroma with scant mononuclear inflammatory cells.

(Left) The gallbladder mucosa is arranged in branching folds lined by simple columnar epithelium without a discrete muscularis mucosa or submucosa. The muscularis propria lies beneath the mucosal folds. (Right) Mucosal herniations through the gallbladder wall are known as Rokitansky-Aschoff sinuses . These irregularly shaped tubular structures are lined by simple columnar or cuboidal epithelium and are often present in gallbladders with chronic cholecystitis.

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebbI

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

(Left) This low-power view of the pancreas shows its lobular parenchyma composed of acinar cells with interspersed islets and scant stroma. Interlobular ducts are lined by cuboidal-columnar epithelium. (Right) The intralobular ducts are lined by cuboidal epithelium. The exocrine acinar cells have basophilic to amphophilic cytoplasm with apical eosinophilic zymogen granules . Centroacinar cells are small and round with pale cytoplasm .

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HEPATOBILIARY SYSTEM

rrss Autopsy Findings rrss Frequent e e e e k k k k o o o o o o o o o o b b b b eebb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

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(Left) The cut surface of this liver shows innumerable metastatic deposits with patchy necrosis in a patient with breast cancer. (Right) The cut surface of this liver shows diffuse green discoloration due to cholestasis in a patient on total parenteral nutrition.

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) The cut surface of this pancreas shows a masslike area of fibrosis with patchy necrosis due to chronic pancreatitis. (Courtesy D. Rubin, MD.) (Right) Hemangiomas are the most common benign tumor of the liver. The cut surface is red and spongy with fibrotic foci . Thrombosis and calcification were present microscopically in these areas. (Courtesy D. Rubin, MD.)

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

(Left) A large black pigmented stone was present in this gallbladder with acute and chronic cholecystitis. The mucosa is erythematous and ulcerated with a green purulent exudate , and the wall is markedly thickened. (Right) Adenomyoma of the gallbladder fundus (a.k.a. adenomyomatous hyperplasia, diverticulum) is a submucosal nodule , often with an overlying mucosal outpouching or "dimple" . The cut surface may appear multicystic.

Autopsy Fundamentals: Autopsy Performance

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: s s p t p t hhtt GENITOURINARY SYSTEM

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s r s r e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t ht hht DEFINITIONSh Horseshoe kidney is the congenital and usually asymptomatic fusion of the inferior poles of the kidneys. The isthmus of the fused kidneys is usually found just below the inferior mesenteric artery.

Normal Anatomy

Urinary tract: Kidneys, ureters, bladder, urethra Female genital tract: Vagina, cervix, uterus, fallopian

s r s r e e k ook o o b eeb

Urothelial carcinoma can arise in the calyces, pelvis, ureters, and bladder. It is often papillary and may be multifocal.

Use fingers or forceps to strip perinephric fat and renal capsule medially toward renal hilum Continue to strip medially to expose renal vessels and ureter Follow ureter inferiorly Dissection of pelvic organs Insert nondominant hand into retropubic space Work hand down into pelvis Palm of hand is now anterior to bladder Encircle pelvic organs with fingers Fingers should sit against coccyx and behind rectum Use upward and anterior traction to remove pelvic organs from pelvic walls This motion will be accompanied by a sucking sound Pull pelvic organs upwards and posteriorly to create a space behind pubic bone While maintaining traction on pelvic organs, use dominant hand to insert scalpel into retropubic space as inferiorly as possible (below cervix/prostate) Carefully cut across inferior attachments of pelvic organs (urethra, vagina, rectum) Scalpel blade will not be visible Take care to keep nondominant hand clear of scalpel blade Transect right and left common iliac arteries Kidneys and rest of genitourinary tract can now be removed en bloc or piecemeal Testes are removed through inguinal canal

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m DISSECTION . . m m t t . . / / t t / / / / : : / / : : ss ss Virchow (Piecemeal) p Evisceration p t t p p t t t t hht hht

tubes, ovaries Male genital tract: Prostate, seminal vesicles, vas deferens, testes

Aorta exposed after abdominal organs removed

Kidneys and adrenals located in perirenal fat on either side of abdominal aorta Remove left adrenal gland Located in perinephric fat at superomedial pole of kidney, applied closely to lateral aspect of aorta Incise perinephric fat adjacent to aorta at level between celiac and superior mesenteric artery (SMA) to expose adrenal Adrenal will have tan-pink lobulated appearance Dissect adrenal from surrounding kidney and fat Remove right adrenal gland Located in perinephric fat at superomedial pole of kidney, at level of SMA, tucked behind inferior vena cava (IVC) Transect IVC, insert finger into lumen, and rotate it laterally Incise perinephric fat in IVC bed at level of SMA to expose adrenal Dissect adrenal from surrounding kidney and perinephric fat Expose kidneys Incise lateral aspect of perinephric fat to expose dark red renal cortex covered by renal capsule Incise renal capsule along lateral aspect of kidney

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt Rokitansky Evisceration (en Bloc) Technique

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht Dissect heart, respiratory tract, liver, and

gastrointestinal tract away from organ block Remove adrenal glands as described above under Virchow technique Place organ block on cutting board, anterior surface down, posterior surface facing you

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

Incise perinephric fat along its lateral aspect until

reaching dark red renal cortex Incise renal capsule over lateral aspect of kidney Use forceps or fingers to strip perinephric fat and renal capsule medially toward hilum Continue to strip fat to reveal renal vessels and ureters Follow ureters to bladder Dissect rectum gynecologic tract from bladder Alternatively in males, leave rectum attached and open it longitudinally Kidneys can be dissected from left attached to aorta and bladder

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Autopsy Fundamentals: Autopsy Performance

GENITOURINARY SYSTEM Bisect cervix and uterine corpus along right and left lateral aspects into anterior and posterior halves 2nd alternative Open cervix and uterus anteriorly with Y-shaped incision Insert scissors into cervical canal and open cervix anteriorly Open endometrial cavity by extending cervical incision toward right and left cornua Serially section ovaries

Dissection of Male Urogenital Tract

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Dissection of Kidneys, Ureters, and Bladder (2 Alternatives) 1st alternative: Intact urinary tract attached to aorta

and bladder Open aorta along its posterior aspect from superior to inferior Insert scissors into renal artery ostium and open renal artery into renal hilum Bisect kidneys in coronal plane leaving 1/2 attached to renal artery and ureter Using fine scissors, open ureter to its junction with bladder Open urethra and bladder anteriorly; probe distal ureter into bladder Make serial sections through detached 1/2 of kidney parallel to original cut Make similar sections in attached 1/2 of kidney, taking care to leave a section attached to renal artery and ureter Advantages: Preserves normal anatomic relationships (for presentation to clinicians or photography) Disadvantages: More labor intensive; makes accurate weighing of kidneys more difficult Some weigh detached 1/2 of kidney and double weight Some dangle attached kidney onto weighing pan 2nd alternative: Piecemeal dissection Transect renal artery close to renal hilum Transect right ureter close to renal hilum and left ureter a few cm from hilum Allows for identification ("left is long") Open ureters with fine scissors Open urethra and bladder anteriorly Probe ureters into bladder Advantages: Faster; allows for accurate kidney weights Disadvantages: Disrupts normal anatomic relationships

Remove rectum from posterior aspect of bladder and

prostate Open prostatic urethra anteriorly into bladder Dissect adherent soft tissue from posterior aspect of prostate to expose seminal vesicles and vas deferens Bisect seminal vesicles into anterior and posterior halves Serially section prostate from inferior to superior Serially section testes

The following are suggestions for sections of grossly

normal organs Some authors suggest fewer or no sections of grossly normal organs; others suggest more sections Local preferences will dictate number of histologic sections submitted for histology Always take additional sections of gross abnormalities as indicated by individual case Kidneys 1 section from each kidney to include renal cortex and medulla Adrenals Complete cross section to include cortex and medulla Bladder: 1 full thickness section Prostate: 1 representative section Testes: 1 representative section Gynecologic tract 1 section of cervix 1 section of cervix to include squamocolumnar junction 1 section of uterus including endo- and myometrium Representative section of ovary and fallopian tube in 1 cassette

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Dissection of Gynecologic Tract

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External Examination General

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Detach gynecologic tract (vaginal cuff, cervix, uterus, fallopian tubes, ovaries) from bladder and rectum Open vaginal cuff along its right and left lateral aspects to expose cervix Open cervix and uterus 1st alternative

Chronic renal failure (CRF) Muscle wasting Dry, brittle hair Sallow, gray-yellow skin Dialysis catheter, fistula Abdominal distension and ascites in ovarian malignancy Skin

Autopsy Fundamentals: Autopsy Performance

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Malar rash of systemic lupus erythematosus Petechial hemorrhages associated with microangiopathy (DIC, TTP, HUS) Ulcerations associated with calciphylaxis Pallor associated with anemia External genitalia Male Penis: Inflammation, masses Scrotum: Testes (undescended?), masses, fluid accumulations Female Vulva: Inflammation, masses

Internal Examination Body cavities

Ascites and peritoneal nodules in ovarian malignancy Cardiovascular Fibrinous ("bread and butter") pericarditis and pericardial effusion in CRF Hypertensive nephrosclerosis Cardiomegaly and left ventricular hypertrophy Renal arterial changes (atherosclerosis, fibromuscular dysplasia) Lungs: Pulmonary edema and congestion in renal failure Kidneys Horseshoe kidney: Inferior poles of kidneys connected; 1 in 400-800 births; usually asymptomatic Renal cysts Few, small: Common and clinically insignificant Diffuse replacement: Adult polycystic kidney disease (enlarged kidneys with large cysts); dialysis kidney (normal-sized kidneys, cysts < 0.5 cm) Hypertensive nephrosclerosis Finely granular cortical surface Infarcts: Wedge-shaped depressed cortical lesions, often embolic Ischemic injury Pale, usually patchy cortical areas, congested medullae, petechiae Nephrolithiasis: Common cause of obstruction in young adults Hydronephrosis: Dilated pelvis and calyces thinned renal cortex Abscesses: Tan-yellow cortical lesions with hyperemic borders Renal tumors Metastatic tumors: Most common malignant renal tumors found at autopsy; especially from lung and breast; often bilateral Renal cell carcinomas: Cortical, tan-yellow, variegated, hemorrhagic, may be large Angiomyolipomas: Fatty yellow tumors; can be associated with tuberous sclerosis Renomedullary interstitial cell tumors (a.k.a. medullary fibromas): Gray-white, small Ureters and pelvis Bifid or duplicated ureters Hydroureter: Dilated, sometimes tortuous ureters; secondary to obstruction

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Tumors: Predominantly urothelial carcinomas

Bladder

Urachal remnants/cysts: At apex of bladder Cystitis: Hyperemic mucosa Obstructive changes: Distended trabeculated bladder Stones Tumors Urothelial carcinoma: Most common; typically gray-white and papillary; may be multifocal Less commonly: Squamous cell carcinoma, small cell carcinoma Prostate Hyperplasia Enlarged, classically symmetrical gland with bulging cut surface Common cause of urethral obstruction and obstructive changes in bladder Tumors Almost exclusively adenocarcinoma Typically minimal gross changes in prostate gland Metastases (bone, lymph nodes) usually easier to see Urethra Posterior urethral valves: Can be associated with hydroureter and hydronephrosis Gynecologic tract Pelvic inflammatory disease Endometriosis Benign tumors Cervical and endometrial polyps Uterine leiomyomas Ovarian cystadenomas, cystadenofibromas, mature teratomas Malignant tumors Cervix: Squamous cell, adenocarcinoma Endometrium: Adenocarcinoma, carcinosarcoma Myometrium: Leiomyosarcoma Ovaries: Surface epithelial tumors, germ cell tumors, stromal tumors Testes Cryptorchidism Hydrocele Orchitis Tumors Germ cell tumors: Seminoma, nonseminomatous, mixed Lymphoma: Especially in patients older than 60 Hepatobiliary Hepatic cysts common in patients with polycystic kidney disease

Lim AKh: Diabetic nephropathy - complications and treatment. Int J Nephrol Renovasc Dis. 7:361-81, 2014 Roy A et al: Common and uncommon bilateral adult renal masses. Cancer Imaging. 12:205-11, 2012 Winterberg PD et al: Acute kidney injury: the beginning of the end of the dark ages. Am J Med Sci. 344(4):318-25, 2012 Levin A: Clinical epidemiology of cardiovascular disease in chronic kidney disease prior to dialysis. Semin Dial. 16(2):101-5, 2003

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GENITOURINARY SYSTEM

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(Left) The adrenal glands, buried in perinephric fat, can be difficult to locate. They sit at the superomedial aspect of the kidneys. Their medial borders abut the inferior vena cava (right) and aorta (left) around the level of the celiac and superior mesenteric arteries. (Right) The left perinephric fat is incised near the superomedial aspect of the kidney, adjacent to the aorta, and at the level of the superior mesenteric artery to expose the left adrenal.

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(Left) Removal of the pelvic organs cannot be done entirely under direct visual inspection. The nondominant hand must be introduced into . the retropubic space The thumb and fingers should then encircle the pelvic organs . (Right) Upward traction is applied to the pelvic organs. This is accompanied by a sucking sound. While maintaining traction, use the scalpel to (blindly) transect the inferior attachments of the pelvic organs below the cervix/ prostate.

Autopsy Fundamentals: Autopsy Performance

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Urinary Tract Gross Pathology

(Left) Renal cell carcinoma, the most common renal malignancy, arises in renal cortex and has a variegated yellow cut surface, often with evidence of hemorrhage and necrosis . It has a propensity for bony metastases. (Right) Ureaseproducing bacteria, such as Proteus, form ammonia and hydroxide from urea, alkalinize the urine, and promote the formation of large magnesium ammonium phosphate or struvite calculi, so-called staghorn calculi.

(Left) This specimen from a fetal autopsy shows cystic kidneys and bilateral hydronephrosis caused by posterior urethral valves. Posterior urethral valves occur exclusively in males, and approximately 1/3 of children born with this condition progress to endstage renal disease. (Right) Chronic ureteral obstruction leads to hydroureter and hydronephrosis. In this case, renal cortex has been reduced to a membranous sac.

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(Left) This bisected prostate and bladder shows the results of chronic urinary obstruction by prostatic hyperplasia and increased intravesical pressure. Note the trabeculations and bladder diverticula . (Right) Squamous cell carcinoma of the bladder is much less common than urothelial carcinoma and often arises in the the setting of chronic inflammation (chronic catheterization, urinary retention, lithiasis, schistosomiasis). Unlike urothelial carcinoma, it is more common in women.

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Autopsy Fundamentals: Autopsy Performance

GENITOURINARY SYSTEM

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(Left) This bisected testis has been extensively replaced by a dark red hemorrhagic tumor, which histologically proved to be choriocarcinoma. Choriocarcinoma often metastasizes widely and the primary testicular tumor may regress. (Right) This bisected testis is extensively replaced by mature cystic teratoma , which has a variegated solid and cystic cut surface. There is a thin rim of residual uninvolved tissue .

Autopsy Fundamentals: Autopsy Performance

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s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht TERMINOLOGY The sternothyroid muscle is being reflected to reveal the underlying thyroid gland and a parathyroid gland .

The bilobed thyroid consists of 2 lobes connected by an isthmus . A pyramidal lobe is seen in 40%, considered a vestige of the thyroglossal duct. (From DP: Normal Histology.)

Thyroid

Definitions

Includes adrenal, thyroid, parathyroid, endocrine

Removed by incising fascia along posterior aspect (from either upper or lower pole), dissecting free from trachea

Adrenals rs s r s s r r e e e e k k k ooCLINICAL ook CORRELATES o o o o o o b b b b b eeb Clinical Diagnosis of Endocrine Disorderee/e e / e e / / e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p Pertinent Antemortem Labs t t p p t t t t hht hht pancreas, and pituitary

Paired; retroperitoneal, anteromedial to kidneys Identified by careful dissection through

e.g,. Cushing disease, thyroid storm,

hyperparathyroidism, diabetes, acromegaly

Thyroid: TSH, T3, T4, TSI (Graves), antimicrosomal Ab (Hashimoto)

Adrenal: Electrolytes, urine/serum catecholamines, 24hour cortisol, dexamethasone suppression test

retroperitoneal fat until golden-yellow cortex is visualized Right gland inferior to liver En masse (Rokitansky): Approach liver from lateral aspect and reflect to reveal adrenal Piecemeal (Virchow): Easily viewed in retroperitoneal fat as right lobe liver reflected (or deep to porta hepatis as portal structures are cut) Left gland between left kidney and aorta En masse (Rokitansky): Approach from left, posterolaterally from aorta, ~ 2 cm above left renal artery Piecemeal (Virchow): Dissect retroperitoneal fat medial to superior pole of left kidney and inferior to tail of pancreas/splenic artery

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Removed together with neck organ block

Remove sternohyoid and sternothyroid muscles to expose thyroid Parathyroids appear tan-brown Inferior parathyroids often visible even without dissecting thyroid from trachea Inferior to thyroid along anterolateral trachea Precarious in position: Anterior lower pole of thyroid, posterior lower pole of thyroid, or anywhere in anterior cervical fat, extending into mediastinum Superior parathyroids often within superior tracheal fat pad Posterior medial portion of mid thyroid May become visible as thyroid removed

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Identify pancreas inferior to stomach extending between duodenum and spleen

Islets are contained within head, body, and tail of pancreas

Pituitary

Within sella turcica of sphenoid bone, infundibular

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ENDOCRINE SYSTEM

rrssEVALUATION/SECTIONING rrss GROSS e e e e k k k k o o o o Parathyroids o o o Adrenals o o o b b b b eebb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht Thyroid Flat is inactive; cuboidal is secreting; columnar is resorbing colloid

Record size and weight (normal: 4-6 mm, 25-40 mg;

varies with age, race, illness) Cut surface is tan to yellow (depending on fat content) Submit intact or bisect larger glands

Right and left lobes connected by isthmus

Pointed superior and blunt inferior pole of lobes Midline pyramidal lobe (vestige of thyroglossal duct) may be present (40%) Record size and weight (normal: 15-25 g; varies with age, gender, iodine intake, hormonal status, body habitus) Sample right and left lobes, isthmus, any gross pathology

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Cortex organized into 3 zones: Glomerulosa,

fasciculata, and reticularis Glomerulosa: Thin, discontinuous, subcapsular; small cells with scant eosinophilic to amphophilic cytoplasm Fasciculata: Thickest, middle layer; larger cells with finely vacuolated lipid-laden cytoplasm Reticularis: Inner layer, abuts medulla; cells with eosinophilic cytoplasm, arranged in cords Medulla Cells with abundant basophilic granular cytoplasm, vesicular nuclei with clumped chromatin, occasional central nucleoli

s r s r e e k k o o o o o o b b b b e e Endocrine Pancreas / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht Pituitary

Right gland pyramidal and left crescentic in shape Record size and weight (normal: 4-6 g each; varies

with age, gender, stress) Remove surrounding fat for accurate weight Section perpendicular (4 mm slices) to long axis Adrenal cortex normally golden yellow Adrenal medulla: Gray brown, ellipsoid; ~ 10% of adult adrenal gland Submit 2 sections per gland, any gross pathology

Islets throughout gland, ~ 1-2% of adult gland Islands of cells with small amount of amphophilic to basophilic cytoplasm, demarcated from surrounding tissue and with rich capillary network

Anterior (adenohypophysis)

Comprises 80% of adult gland Cells in nests/acini rimmed by sustentacular cells Mixed population of different cell types Reticulin network rich in capillaries Posterior (neurohypophysis) 20% of adult gland Modified glial cells (pituicytes) and neuropil (network of unmyelinated axons)

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Record size and weight (normal: 0.4-0.6 g; varies with pregnancy, multiparity

Ovoid; larger anterior, smaller posterior lobe Bisect gland sagittally through infundibulum, submit both halves

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Adenoma

Asymmetrically enlarged gland with nodular monotonous cell population without fat Hyperplasia All glands enlarged; common in chronic renal failure; malabsorption ( vitamin D)

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NORMAL HISTOLOGY

Parenchymal cells: Chief, oxyphil, clear (rare) cells

Chief: Small, amphophilic vacuolated cytoplasm, central nucleus, in nests and cords with rich capillary network Oxyphil: Larger, abundant eosinophilic granular cytoplasm, in small clusters, with age Clear: Vacuolated cytoplasm due to abundant glycogen, uncommon Stroma adipose tissue and fibrovascular network Adipose with age in hyperactive gland Adult gland 20-40% adipose tissue

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Parathyroid

Multinodular goiter

Enlarged thyroid containing multiple nodules Weight may reach or exceed 2 kg Nodules may be hemorrhagic, cystic, calcified, &/ or associated with fibrosis Colloid nodule Well-circumscribed glassy-appearing nodule

Adrenals

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Follicles containing central colloid; lined by monolayer of epithelial cells Capillary network surrounds follicle Follicular cells change shape with activity

Cortical adenoma

Well-circumscribed yellow nodule within adrenal cortex Size usually < 5 cm and weight usually < 50 g Most arise from zona fasciculata Metastatic carcinoma

Autopsy Fundamentals: Autopsy Performance

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rrss e e k k o o o Area Examined o eebb Head and integument

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Breasts

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Genitalia

Extremities

Alopecia (scalp and lateral eyebrows)

Hypothyroidism, hypopituitarism (decreased TSH)

Dry, brittle hair

Hypothyroidism, hypopituitarism (decreased TSH)

Hirsutism

Adrenal excess (hypercortisolism)

Exophthalmos

Hyperthyroidism (Grave disease)

Periorbital puffiness

Hypothyroidism, hypopituitarism (decreased TSH)

Coarse facial features

Hypothyroidism, hyperpituitarism (increase GH), hypopituitarism (decreased TSH)

Frontal bossing

Hyperpituitarism (increased GH)

Prognathism

Hyperpituitarism (increased GH)

Rounded (moon) face

Adrenal excess (hypercortisolism)

Acne

Adrenal excess (hypercortisolism)

Hyperpigmentation of sun-exposed skin

Adrenal insufficiency, pituitary insufficiency (ACTH deficiency)

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Abdomen

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External Examination Clues to Endocrine Disease

Hypopigmentation

Pituitary insufficiency (decreased MSH)

Thin skin with bruising

Adrenal excess (hypercortisolism)

Palpable anterior thyroid

Hyperthyroidism (Grave disease), goiter, adenoma, carcinoma

Palpable lateral neck mass(es)

Parathyroid adenoma, hyperplasia

Galactorrhea

Pituitary excess (prolactin) (women)

Darkened areola

Adrenal insufficiency, pituitary insufficiency (ACTH deficiency)

Striae

Adrenal excess (hypercortisolism)

Central obesity

Adrenal excess (hypercortisolism), endocrine pancreas insufficiency (diabetes mellitus, especially type 2)

Necrolytic migratory erythema (often involves perineum and buttocks)

Endocrine pancreas excess (glucagon)

Testicular atrophy and softening

Hyperpituitarism (prolactin)

Pretibial myxedema

Hypo-/hyperthyroidism

Necrobiosis lipoidica diabeticorum (usually pretibial)

Endocrine pancreas insufficiency (diabetes) (rare complication, usually women)

Large hands and feet

Hyperpituitarism

Clubbing of fingers and toes

Hyperthyroidism (rare)

Foot ulcers

Endocrine pancreas insufficiency (diabetes)

Gangrene

Endocrine pancreas insufficiency (diabetes)

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Metastatic tumor deposits are grossly distinct from surrounding adrenal but are usually well circumscribed

ANCILLARY TESTS

s s r s s Serum err r e e e k k k Pancreas ooEndocrine ook o o oo o o b b b b b eeb e e / / e e / / e e e e m m Pituitary .t.m .t.m t t / / / / / / : : / / : : Vitreous and CSF s s s s p p t t p p t t hhtt hhtt Urine Hormone assays

Amyloid in islets of type 2 diabetics (islet amyloid polypeptide amylin)

Micro- (< 10 mm) and macroadenomas

Soft, well-circumscribed tan nodule May be confined to sella or extend out (suprasellar) Micro: Uniform polygonal cells without reticulin network May be composed primarily of acidophilic, basophilic, or chromophobic cells Rathke cleft cysts (30% of pituitary glands) Usually only seen microscopically; occur in adenohypophysis Cyst lined by ciliated cuboidal cells, occasional goblet cells and anterior pituitary cells Salivary gland rests in posterior pituitary may be seen at junction with infundibulum

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TSH shown to be stable post mortem Mostly specific forensic use, not routine Glucose Spuriously low (postmortem glycolysis)

More stable for glucose and electrolytes

Urine glucose and protein relatively stable post mortem

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht SELECTED REFERENCES

1. 2.

Palmiere C et al: Postmortem chemistry update part I. Int J Legal Med. 126(2):187-98, 2012 Elias AN et al: Pathology of endocrine organs in chronic renal failure--an autopsy analysis of 66 patients. Int J Artif Organs. 7(5):251-6, 1984

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ENDOCRINE SYSTEM

rrssExcised Endocrine Organs rrss In Situ, e e e e k k k k o o o o o o o o o o b b b b eebb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

(Left) This illustration shows the positioning of the parathyroid glands along the posterior surface of the thyroid gland. The superior glands are more uniform in location than the inferior glands. (Right) Right inferior parathyroid gland embedded within adipose tissue shows a normal tanbrown appearance. Note that this gland is located somewhat lateral to the thyroid, not along the posterior surface. Inferior parathyroid glands can be variable in position.

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) This is an in situ view of the right adrenal gland . It is located beneath the right lobe of the liver , slightly lateral to the liver hilum (note gallbladder ) and inferior to the diaphragm . (Right) The left adrenal gland is superomedial to the left kidney and inferior to the pancreas. The left adrenal vein is visualized as it courses towards the left renal vein. The tanwhite tissue surrounding the adrenal is the adrenal capsule.

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s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

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(Left) The pituitary gland sits in the base of the skull. The infundibulum (stalk) protrudes through the dura overlying the sella turcica . The cut ends of the optic chiasm and the internal carotid arteries demonstrate the proximity of these important structures to the pituitary. (Courtesy R. Rhodes, MD.) (Right) This gross image of a normal pituitary gland demonstrates its ovoid shape and the attached stalk . The normal pituitary weighs between 0.4-0.6 gms.

Autopsy Fundamentals: Autopsy Performance

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: s s p t p t hhtt ENDOCRINE SYSTEM

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s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Normal Histology

(Left) The adenohypophysis has eosinophilic , basophilic , chromophobe , and sustentacular cells with surrounding capillaries. Hormone secretion can be determined by immunohistochemistry. (From DP: Normal Histology.) (Right) The pancreas has ~ 1 million islets , which are distinct cell clusters with a rich vascular network . They contain , , , and PP cells producing insulin, glucagon, somatostatin, and pancreatic polypeptide, respectively. cells are the most numerous.

(Left) Follicles are the functional thyroid unit and comprise a single layer of follicular cells around colloid . There is a microscopic nodule and a small colloid nodule present. (From DP: Normal Histology.) (Right) The parenchymal cell of the parathyroid is the chief cell . Adipose tissue and fibrovascular tissue comprise the stroma. Fat increases with age and decreases with activity of the gland. (From DP: Normal Histology.)

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

(Left) The adrenal cortex is organized into 3 layers from the capsule toward the medulla: The glomerulosa , fasciculata , and reticularis . The fasciculata comprises the majority of the cortex, and the cells contain abundant lipid that imparts the yellow color to the adrenal gland macroscopically. (From DP: Normal Histology.) (Right) The adrenal medulla is composed of large polygonal cells with abundant basophilic cytoplasm . (From DP: Normal Histology.)

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rrss Autopsy Findings rrss Frequent e e e e k k k k o o o o o o o o o o b b b b eebb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

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(Left) This asymmetrically enlarged and multinodular thyroid represents a multinodular goiter. An enlarged gland without nodules is a simple goiter. Multinodular goiter can reach marked sizes 2 kg. (Right) This enlarged parathyroid gland (1.5 cm) was the only enlarged gland identified and represents a small adenoma.

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) These islets of a type 2 diabetic contain hyaline-appearing amyloid . The amyloid protein is islet amyloid polypeptide (amylin). The cells can be obscured when large amounts of amyloid are deposited. (Right) This well-circumscribed yellow nodule within the adrenal gland (residual cortex ) represents an adenoma. Although slightly larger than most identified at autopsy, this adenoma demonstrates a classic appearance, except for the small focus of hemorrhage .

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s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

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(Left) The adrenal glands are often autolyzed at autopsy, as demonstrated here. The autolysis affects the adrenal medulla before the cortex, often leaving a space surrounded by the residual adrenal cortical tissue . (Right) This coronal section of the brain reveals a large, brown-appearing pituitary adenoma attached to the optic chiasm . This proximity to the optic chiasm accounts for the visual disturbances caused by adenomas.

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt CENTRAL NERVOUS SYSTEM

rrss e e k k o o o o eebb

s r s r e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht TERMINOLOGY Inferior view of a brain shows all the cranial nerves that were cut during removal, except the olfactory . The internal carotid arteries are also seen . There is a collection of blood over the left inferior cerebellum .

Definitions

Brain and spinal cord

Atherosclerosis of the left vertebral artery is apparent from this inferior view of the brain. The mamillary bodies are also seen (a landmark for coronally sectioning the brain).

Peel skin forward to just above brow anteriorly and below occiput posteriorly Divide temporalis muscle on each side along line connecting pinna and eyebrow Scrape clean path for saw pass-through (exposing underlying bone) Remove skull cap using vibrating saw cutting in semicircle from temporal to frontal, then from temporal to occiput Triangular notch ensures fit after autopsy With hand support posteriorly, incise falx, vessels, and cranial nerves (except olfactory) to release brain from vault Transect upper cervical cord and remove from body Strip dura from skull base (examine for fractures) and calvaria (examine dural sinuses) Remove pituitary by unroofing (fracturing) the dorsum sellae, incising around diaphragm Fixation 10-20% formalin for 7-10 days before sectioning Hang by string under basilar artery Dehydrate blocked sections 24 hours in 70% ethanol, then 24 hours in 95% ethanol before routine processing and embedding Brain cutting Remove cerebellum by transecting midbrain horizontally at level of cerebellar peduncles Section cerebellum and pons axially in 5 mm sections Divide brain into anterior and posterior halves for coronal sectioning Hemispheres facing down on cutting board Initial cut through mamillary bodies Aim for symmetry using temporal lobe horns as a guide Incise midbrain on 1 side to help with orientation Section each half coronally in 1 cm sections Lay out sections serially

s s r r s s r r e e e e k k ook ook o o o o o o b b b b b eeb MACROSCOPIC FINDINGS ee/e e / e e / / e e m m . . m m t t . . External Examination / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht Abbreviations

Central nervous system (CNS)

Trauma (pattern of injury)

Bruising, lacerations Fractures Bruising around eyes (raccoon sign), mastoid: Basal skull fracture Limb musculature Asymmetry, atrophy: Stroke, demyelination, neurodegenerative disease Deformities Facial dysmorphism Skin abnormalities (e.g., caf au lait spots in neurofibromatosis type 1) Cleft lip/palate: Septo-optic dysplasia Debilitation Feeding tube Decubitus ulcers Anoxia Evidence of resuscitation (rib fractures, automated external defibrillator [AED] pads, etc.) Survival for at least 6-12 hours needed for microscopic evidence

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Brain

Block between shoulder blades helps position skull Bitemporal skin incision from pinna to pinna across vertex scalp

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Invert each section from one of the halves to maintain right-left orientation in serial sections Spinal cord Removed en bloc from cervical to cauda equina, using either anterior or posterior approach Anterior approach (most common, allows ganglia and nerve roots to be removed) Place body supine with block between shoulders Dissect paraspinal muscles away from all vertebral pedicles Use vibrating saw to cut line connecting pedicles to body; adjust angle of cut as vertebra change shape Use wedge hammer to pry vertebral bodies up and expose canal Posterior approach (for craniocervical anomalies, neck injuries, and meningoceles) Place body prone with block under sternum Incise skin along line of spinous processes Dissect muscle and soft tissue to expose vertebral laminae Use vibrating saw to cut line at laminae, lift posterior bony plate to expose canal Use saw/rongeurs to expose roots and ganglia at each level Cord removal Incise dura lengthwise from neck to sacrum Cut dura circumferentially at level high in neck Gently tug high cord down through high neck Continue caudally, freeing cord and dura from canal "Bread-loaf" section entire cord at 5 mm intervals Vertebral artery Should be examined in traumatic deaths (may also be spontaneous) Blood in cisterna magna may be seen with vertebral artery injury Travels in transverse foramina of cervical vertebrae (expose using rongeurs) Enters foramen magnum Fetal CNS Incise along fontanelles and sutures and expose skull in butterfly fashion Removal similar to adult, but tissue is extremely soft Use posterior spine approach in Dandy-Walker cyst, occipital encephalocele, craniocervical abnormalities

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Basal ganglia, pons, and cerebellum Common locations for lacunar infarcts Lentiform nuclei atrophy, discoloration: Neurodegenerative, toxic Caudate atrophy: Huntington disease Midbrain substantia nigra and locus ceruleus Loss of pigmentation in Parkinson disease and multisystem atrophy Pediatric Congenital malformations Choroid plexus/germinal matrix hemorrhage Periventricular white matter discoloration/ cavitation Cerebral vasculature Carotid atherosclerosis Circle of Willis (atherosclerosis, aneurysm) Vertebrobasilar system (atherosclerosis, dissection) Spinal cord Softening/darkening may indicate hemorrhage, ischemia Watershed between anterior 2/3 and posterior 1/3 of each cross section Craniocaudal watersheds at T1-T4 and L1-2 (few collaterals) White matter discoloration: Demyelinating disease Atrophic anterior roots: Amyotrophic lateral sclerosis, polio Traumatic laceration, contusions, or old cavitation (syrinx) Sections to be submitted Sample any suspected lesions; corresponding sections from other side may be taken for comparison Routine sections Cortex and white matter (frontal, temporal, parietal, occipital), e.g., superior midfrontal gyrus "Watershed" areas (frontotemporal-anterior/ middle cerebral arteries, parietooccipital-middle/ posterior cerebral arteries) Basal ganglia, thalamus, mamillary bodies Hippocampus Midbrain Pons (locus ceruleus) Cerebellum with vermis &/or deep nuclei Cervical, thoracic, and lumbar cord (with ganglia, if possible) Pituitary gland, bisected along long axis and submitted en face Neurodegenerative disease (in addition to routine) Cingulate, insula Amygdala Nucleus basalis Medulla (inferior olivary nucleus) Motor cortex Staining Routine sections through brain are stained with H&E alone or also stained with Luxol fast blue (LFB) to highlight myelin; these H&E/LFB sections show gray matter as pink and white matter as blue Sections without expected white matter, such as pituitary gland, can be stained with H&E alone

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / General Features : : s s s s p p t t p p t t hhtt hhtt Surface

Hemisphere symmetry: Stroke, degenerative disease Gyral effacement, sulcal prominence Cerebellar vermis atrophy: Chronic alcohol abuse Tonsillar, uncal herniation Meninges Opaque, purulent: Meningitis Cut sections Grey-white junction: Focally indistinct in ischemia, demyelination, dysplasias Site of subtle metastatic tumor, emboli, thrombi Ventricle enlargement and hippocampal atrophy: Neurodegenerative, seizure

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Autopsy Fundamentals: Autopsy Performance

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p MICROSCOPICttFINDINGS t p p t t t ht hht General Featuresh ANCILLARY TESTS In patients > 65 years of age, even without clinical history of dementia, routine sections through frontal and temporal cortex and hippocampus can be stained with Bielschowsky silver stain to screen for age-related amyloid plaques and neurofibrillary tangles

6-layered cortex and underlying white matter with

normal myelination Pediatric brains: Cortical maturation, myelination matched for age Basal ganglia: Evidence of arteriosclerosis or Alzheimer type II astrocytosis (metabolic encephalopathy) Loss of neurons (or "red" neurons) in susceptible areas: Cerebral hypoxia CA1 region of hippocampus Cerebellar Purkinje cells Increased cellularity indicating neoplasia or gliosis Intraneuronal or intraglial inclusions Neurodegenerative Inflammatory Metabolic Areas of necrosis: Infarction or neoplasia

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1 normal NaOH Autoclave (121 C gravity displacement of 134 C porous load) Rapid triage process sample from frontal lobe 100% formic acid for 1 hour, formalin for 48 hours, then processed If spongiform encephalopathy, then continue precautions for brain cutting

Lumbar Puncture

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m EEG t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht CT/MR Increased WBC count, abnormal protein or glucose, indicating infection

CSF cultures for bacteria, fungi, acid-fast bacilli, PCR for viruses

CSF may show malignant cells in carcinomatous meningitis or ventricular tumors

Premortem EEG may indicate seizure disorder, focal lesion, prion disease

Mass lesions, skull fractures (CT), meningeal enhancement, infarcts/hemorrhages

Angiography s s r rrs s r e e CLINICAL CORRELATES e e k k k History k ooNeurologic o o o o o o o o b b b EMG/Nerve Conduction Studies b b eeb e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss SELECTED REFERENCESpss Systemic Disease tp p t t hht hhttttp Conventional or CT angiogram/MR angiogram (vasculitis, vascular malformations)

Handedness, neurological disease, risk factors or trauma, swallowing difficulty/aspiration (neurodegenerative)

Diabetes, atherosclerotic risk factors (cerebrovascular

disease) Atrial fibrillation, coagulopathy, endocarditis (stroke) Hepatic, renal failure (encephalopathy) Drugs (anticonvulsant, immunosuppression) Shock, volume loss (watershed ischemia) Vasculitis, sarcoid, etc.

Denervation may indicate peripheral or central (cord or roots) nervous system disease

Center for Disease Control and Prevention Guidelines: Creutzfeldt-Jakob Disease Infection-Control Practices. http://www.cdc.gov/ncidod/dvrd/cjd/ qa_cjd_infection_control.htm. Published August 23, 2010. Accessed May 12, 2014 Finkbeiner W et al: Autopsy Pathology: A Manual and Atlas. 2nd Ed. Philadelphia: Saunders Elsevier, 2009 Waters B: Handbook of Autopsy Practice. 4th Ed. Totowa: Humana Press, 2009 Love S: Post mortem sampling of the brain and other tissues in neurodegenerative disease. Histopathology. 44(4):309-17, 2004 Gilles FH: Perinatal neuropathology. In: Davis RL et al: Textbook of Neuropathology. Baltimore: Williams & Wilkins. 331-85, 1997 Budka H et al: Tissue handling in suspected CreutzfeldtJakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol. 5(3):319-22, 1995 Adams VI: Autopsy technique for neck examination. II. Vertebral column and posterior compartment. Pathol Annu. 26 Pt 1:211-26, 1991

s s r r s s r r e e e e k k ook ook o o oo o o b b b b b eeb SPECIAL PRECAUTIONS e e / / e e / / e e e e m m .t.m .t.m Suspected Prion Disease t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt 2. 3. 4.

Incidence and transmission risk is extremely low Universal precautions (mask, eye protection, disposable gown, and double gloves)

Extra precautions

Dedicated room Dedicated or disposable instruments Isolation tent to collect bone dust PAPR, HEPA filter breathing apparatus Disposable pads to prevent cuts, punctures Tared container (weighed before and after brain submerged) Formic acid formalin fixation Cleaning instruments and surfaces NaOCl (bleach) solution of 20,000 ppm

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

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CENTRAL NERVOUS SYSTEM

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(Left) Gross picture at autopsy shows the scalp incised and reflected to expose the skull and dissected temporalis muscle creating a path for the vibrating saw. The saw lines can also be seen. (Right) This image demonstrates removal of the skull cap and cutting through any dural attachments. A large defect is also seen from prior craniectomy.

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) Gross photo viewed from the right side shows the appearance of the brain after removal of the skull cap and dura. Note diffuse subarachnoid hemorrhage . (Right) Anterior attachments, including olfactory tracts, infundibulum, and optic chiasm have been cut. Attachments at the middle cranial fossa and posterior dural attachments can now be cut. Note the bilateral subarachnoid hemorrhages .

s r s r e e k ook o o b eeb

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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(Left) This portion of dura, peeled from the skull cap, through shows serial cuts the superior sagittal sinus to assess patency and presence of clots. (Right) This patient with previous and drain craniectomy placement presents more of a challenge for brain removal. The standard approach to removal should still be followed as closely as possible, cutting around or through any surgical incisions.

Autopsy Fundamentals: Autopsy Performance

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: s s p t p t hhtt CENTRAL NERVOUS SYSTEM

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Brain Cutting

(Left) This superior view of the brain after stripping the meninges allows better assessment of landmarks. Note the omega () shape of the hand area of the motor (precentral) gyrus . (Right) Right lateral view shows fixed autopsy brain with meninges stripped. This gyral pattern is normal (in comparison to the gyral atrophy and widened sulci seen in dementia, especially in the frontal and temporal lobes in frontotemporal dementia). The cerebellum has not yet been removed.

(Left) Lifting the brainstem away from the cerebrum, the cerebellum can be removed by a horizontal midbrain incision through the cerebellar peduncles. (Right) The 1st step in brain cutting is to coronally separate the anterior and posterior halves of the cerebrum. A coronal cut is made directly downward through the mamillary bodies . The anterior temporal lobes can be used as a guide to ensure a symmetric cut.

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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(Left) Scoring either the right or left side of the brainstem can be performed so that laterality can be established on microscopic sections. (Right) Alternatively, the cerebellum can be removed after the coronal cut through the hemispheres. Using a scalpel, a straight horizontal incision is made caudal to the mamillary bodies , through the midbrain (cerebellar peduncles).

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rrssCutting Brain e e k k o o o o eebb

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht (Left) After the brain is divided in half, each half is sectioned coronally with the flat side down (anterior half shown here). A long blade is used to make 1 cm slices through the brain. If possible, avoid jagged sawing motions. (Right) One method for sectioning the cerebellum is to first separate brain stem from cerebellum. A scalpel is used to severe vascular and meningeal attachments and then cut through the middle on cerebellar peduncle each side.

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) Photograph shows the cerebellum after removal of the brainstem. Note the roof of 4th ventricle is cleanly separated from the cerebellar vermis and the middle peduncle is viewed en face. (Right) In this pediatric brain, the brainstem and cerebellum are kept intact and sectioned horizontally together. This may allow for better evaluation of suspected brainstem or cerebellar congenital malformations, such as a Dandy-Walker cyst.

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s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

(Left) Photograph shows axial sections through the brainstem and cerebellum in ~ 5 mm sections from rostral to caudal. Note the pigmentation of the substantia nigra and locus ceruleus . (Right) In the anterior approach to cord removal, saw cuts are made at pedicles . In the posterior approach, the cut is made through the lamina . The angle of the saw cuts needs to be adjusted, as cervical, thoracic, and lumbar vertebrae have different shapes.

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt PERIPHERAL NERVOUS SYSTEM

rrss e e k k o o o o eebb

s r s r e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht CLINICAL IMPLICATIONS To remove a sural nerve sample, draw an arcuate line over the ankle posterior to the lateral malleolus, incise the skin, isolate the subcutaneous sural nerve, and remove a segment of at least 5 cm.

H&E stain of a sural nerve biopsy in cross section shows 6 fascicles with marked axonal loss. The small fascicles are surrounded by moderate epineurial and mild perineurial fibrosis.

No classic stigmata of NF1 or NF2

Pertinent Antemortem Information Disease or syndrome with neuropathy

s r s r e e k ook o o b eeb

Dissection Techniques

Sural nerve (pure sensory; limited value)

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss Anatomic Correlations p p t t p p t t t t hht hht Biopsy report of peripheral neuropathy Muscle biopsy report of neurogenic atrophy Electrophysiology Nerve conduction studies Electromyography (muscle innervation status) Magnetic resonance imaging Compartment syndrome involving nerve

Peripheral neuropathy distribution, e.g., dermatomes Focal: Compression/trauma, diabetes, vasculitis,

herpes zoster virus, radiation, leprosy, sarcoidosis Multifocal: Demyelination, axonal degeneration Mononeuropathy: Single nerve involvement Mononeuropathy multiplex: Several nerve trunks Polyneuropathy: Acute, subacute/chronic, genetic

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Mark arcuate line over ankle starting 1.5 cm posterior to fibular tip, posterior to lateral malleolus Incise into subcutaneous tissue, gently resect 5 cm Divide for light and electron microscopy Alternatively, remove nerve over gastrocnemius muscle belly Cervical plexus: Spinal nerves C1 (variable), C2-C4 Emerges deep to mid sternocleidomastoid muscle Back of head, part of neck, diaphragm (with C5) Brachial plexus: Spinal nerves C4 (variable), C5-C8, T1 Passes through neck under mid clavicle to axilla Chest, diaphragm, upper limb except trapezius Lumbar plexus: Spinal nerves T12 (variable), L1-L4; upper part of lumbosacral plexus Forms lateral to intervertebral foramina, proceeds through psoas major muscle Leaves pelvis posterior to inguinal ligament, partly as obturator nerve Lower abdomen, buttocks, thigh, knee, genitalia Sacral plexus: Spinal nerves L4, L5, S1-S4 converge with lumbosacral trunk Traverses pelvic bone’s greater sciatic foramen, lies over retrorectal space Pelvis, buttocks, genitalia, lower limb Coccygeal plexus: Spinal nerves S4, S5 and coccygeal nerve Form anococcygeal nerves over levator ani muscle Posterior or anterior removal of spinal cord/dura Include spinal nerve roots, cauda equina, some dorsal root ganglia (DRG)

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

Associated disease: Amyloidosis, vasculitis, systemic

lupus erythematosus, diabetes mellitus, liver disease, uremia, tumor Severe peripheral nerve damage Amyotrophic lateral sclerosis, Guillain-Barr syndrome, toxin Nerve or familial syndrome-associated tumor Malignant peripheral nerve sheath tumor (MPNST) Up to 13% lifetime risk in neurofibromatosis type 1 (NF1) Other NF1-associated malignancy

rrss rrss e e e e k k k k o o o o Gross Evaluation/Sectioning o o o MACROSCOPIC FINDINGS o o o b b b b eebbI Anatomic Features e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: 2 p p t t p p t t t t hht hht Peripheral nerve-associated thickening or mass Schwannomatosis: Late-onset painful schwannomas

Spinal nerve roots, DRG: Note spinal level Peripheral nerve/nerve lesion: Note nerve plexus, trunk, or branch

: s s p t p t hhtt

rrss e e k k o o o o eebb Frequency

External clinical signs Internal exam findings

Autopsy Fundamentals: Autopsy Performance

PERIPHERAL NERVOUS SYSTEM

rrss e e k k o o o o NF1 NF2 o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht Distinguishing Features of NF1 vs. NF2

1/2,500

1/25,000

> 6 café au lait macules, skin fold freckling, Lisch nodules (iris), skin neurofibromas

< 6 café au lait macules, cataracts, rarely skin neurofibromas

Plexiform neurofibromas (arising from underlying nerves), glial heterotopias (rare)

Schwannomas (especially vestibular division of CN8), supratentorial meningiomas, peripheral nerve schwannosis, ependymal/neural ectopia, syringomyelia, atypical glial nests

Associated tumors MPNST, astrocytoma (2-3% lifetime risk), rhabdomyosarcoma, juvenile xanthogranuloma, GIST, carcinoid, pheochromocytoma, medullary thyroid carcinoma

Diffuse astrocytomas (rare)

s s r r s s r r e e e e k k k k o o o o o o o Indications for Sampling Peripheral Nerve at o o o b b b b eebb Autopsy e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht NF1 = neurofibromatosis type 1; NF2 = neurofibromatosis type 2; MPNST = malignant peripheral nerve sheath tumor; GIST = gastrointestinal stromal tumor; CN8 = vestibulocochlear (acoustic) cranial nerve

Guillain-Barr syndrome/chronic inflammatory demyelinating polyneuropathy (CIDP)

History of

Systemic or peripheral nerve vasculitis Amyloidosis Hereditary neuropathy Lipid storage disease Suspicion of Inflammatory neuropathy Paraneoplastic neuropathy

Organ disease: Uremia, liver disease, chronic hypoxia Nutritional: Vitamins B12, B1, B5, and E deficiency Toxic: Alcohol, chloroquine, lead, mercury, vincristine Genetic Hereditary motor sensory neuropathies (HMSN) Hereditary sensory and autonomic neuropathies (HSAN) Porphyric neuropathy Dejerine-Sottas disease Spinocerebellar degenerations (e.g., Friedreich ataxia) Ataxia telangiectasia Storage: Sphingolipidoses, adrenoleukodystrophy Tumors Neurofibromas (NFs), plexiform NFs Schwannoma, plexiform schwannoma Perineurioma MPNST Others: Critical illness polyneuropathy, mitochondrial cytopathy, inflammatory sensory polyganglionopathy

s s r r s s r r e e e e k k ookMICROSCOPIC FINDINGS ook o o o o o o b b b b b eeb Normal Histology e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht SELECTED REFERENCES Peripheral nerve and spinal nerve roots

Connective tissue: Epi-, peri-, endoneurium Axons, Schwann cells, myelin sheaths Neurofilament stain: Unmyelinated axon density Blood vessels Resin semithin sections: Nerve fascicle cross section Large and small myelinated axon density, myelin sheath thickness Teased nerve preparation Myelin sheath thickness, segmental demyelination, myelin ovoids (early wallerian degeneration following axonal lesion) DRG: Epineurium, sensory neurons, satellite glial cells, axons, Schwann cells, myelin, blood vessels

s r s r e e k ook o o b eeb

Farid M et al: Malignant peripheral nerve sheath tumors. Oncologist. 19 (2):193-201, 2014 Hirbe AC et al: Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 13(8):834-43, 2014 Lim SH et al: Systemic therapy inneurofibromatosis type 2. Cancer Treat Rev. 40(7):857-61, 2014 Ferner RE et al: Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol. 115:939-55, 2013 Lloyd SK et al: Neurofibromatosis type 2 (NF2): diagnosis and management. Handb Clin Neurol. 115:957-67, 2013 Vranceanu AM et al: Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a systematic review of the literature. J Neurooncol. 114(3):257-62, 2013 King RHM: Atlas of Peripheral Nerve Pathology. London: Arnold, 1999 Midroni G et al: Biopsy Diagnosis of Peripheral Neuropathy. Boston: Butterworth-Heinemann, 1995

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : Disease/Histologic Findings of Neuropathy s s s s p p t t p p t t hhtt hhtt 2.

3. 4. 5. 6.

Inflammatory demyelinating neuropathy: GuillainBarr syndrome, CIDP

Other inflammatory: Sarcoidosis, perineuritis, insect

bites Infectious: Leprosy, Lyme disease, human immunodeficiency virus, cytomegalovirus Vasculitis: Multisystem vasculitides, isolated peripheral nerve vasculitis Dysproteinemia: Immunoglobulin paraprotein, cryoglobulinemia, multiple myeloma Amyloidosis: Primary, familial Neoplasia associated: Paraneoplastic, infiltrative Endocrine: Diabetes, hypothyroidism, acromegaly

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Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt PERIPHERAL NERVOUS SYSTEM

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Microscopic Features

(Left) OsO stain of 2 teased (separated) sural nerve axons shows remyelination of 1 with a thin myelin sheath compared to the thick normal segment above . The other has myelin ovoids of wallerian degeneration secondary to axonal degeneration. (Right) Toluidine blue stain of a plastic section has axonal loss, large axons with normal myelin sheath thickness , thin sheaths of remyelination including an almost naked axon with little myelin , and regenerative sprouts .

(Left) Lower extremity amputation removed the distal axon of this lumbar spinal cord anterior horn neuron causing reactive central chromatolysis , as seen with an H&E stain. (Right) H&E stain shows "onion bulbs" formed by Schwann cells in CharcotMarie-Tooth disease in a cross section of the cauda equina. These accumulated Schwann cells encircle axons from the lower spinal cord in waves of unsuccessful attempted remyelination following primary or secondary wallerian degeneration.

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

(Left) Luxol fast blue stain of the cauda equina in hereditary motor sensory neuropathies type 1 shows thinly myelinated axons , indicating remyelination and "onion bulbs" with demyelinated axons . (Right) A sural nerve from a patient with Lyme disease caused by Borrelia burgdorferi has chronic inflammatory neuritis, as seen with an H&E stain. Lymphocytes, scattered and in small aggregates , are mostly in the perineurial covering of this fascicle. Epineurial fibrosis shows the chronicity of the lesion.

2 68

: s s p t p t hhtt

: s s p t p t hhtt Autopsy Fundamentals: Autopsy Performance

PERIPHERAL NERVOUS SYSTEM

rrssand Microscopic Features rrss Gross e e e e k k k k o o o o o o o o o o b b b b eebb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

(Left) Immunostain for CD3 shows T lymphocytes in Lyme neuritis along a fascicular blood vessel , scattered in the endoneurium , and in epineurial connective tissue, including in a perivascular space . This chronic inflammation affects axons and their vascular supply. (Right) Large neurofibromas expand multiple nerve roots of the lumbosacral spinal cord in NF1. The lumbosacral spinal cord is still enclosed in the dura with the upper cauda equina visible .

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) Trichrome stain of this plexiform neurofibroma in the eyelid of a 5-year-old girl shows typical sparse cellularity. It surrounds the nerve radicle and expands the perineurium . (Right) This schwannoma of the vestibular division of CN8 is reflected by a probe to lie by the medulla . Vestibular division schwannomas may occur spontaneously and they are very common in NF2. The basilar artery is seen over the belly of the pons.

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

(Left) This schwannoma of the median nerve in the arm displays the compact fascicular Antoni type A and loose Antoni type B areas typical of this benign nerve sheath tumor, as seen with H&E stain. Focal palisading of nuclei is typically found. (Right) A Verocay body, pathognomonic of schwannoma, has repeated picket fence-like cell palisades forming alternating nuclear and cytoplasmic bands aligned in a prominent manner in this H&E stain.

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt INTEGUMENTARY SYSTEM

rrss e e k k o o o o eebb

s r s r e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hhtFINDINGS hht MACROSCOPIC External examination findings at autopsy of a patient with a left ventricular assist device are shown. A recent medial sternotomy scar is present. The driveline exit site is well healed and noninflamed.

External Examination Tattoos

Multiple caf au lait spots represent an important cutaneous manifestation of neurofibromatosis syndromes. (From DP: Familial Cancer.)

Tearing injury through full skin thickness Jagged, irregular edges; often accompanied by bruising May be caused by tangential force or crushing/ blunt force More common on skin overlying rigid bony structures Incised wounds Cuts, punctures, stabbing Traumatic vs. iatrogenic May be stapled, sutured, dressed Burns 1st degree: Scald type, redness, and swelling 2nd degree: Blistering 3rd degree: Charring, full thickness "Rule of 9’s": Surface area of each side of each leg, each arm, abdomen, chest, lower back, upper back, head Scars Well healed: No remaining eschar; fade from redpink to white over time (months to years) Contracture (especially over flexor surfaces of joints) Hypertrophic (keloid): Taut, protuberant, markedly exaggerated fibrotic response Lesions Seborrheic keratosis Raised, hyperpigmented lesions with pasted-on warty appearance "Barnacles of old age": Benign behavior Actinic keratosis Scaly, plaque-like lesion on sun-exposed skin areas Rough, sandpaper-like appearance with discoloration (red or brown) Precancerous squamous lesion Basal cell carcinoma Shiny, pearly skin nodules Sun-exposed or protected skin May be destructive, erosive of adjacent structures

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s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

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May be present on any skin surface Accessible mucosal membranes (e.g., inner lip) may also be tattooed Professional Colorful, intricate fine details; sharp lines, larger areas Homemade Coarse lines, irregular, crude; usually letters or digits Fading may occur with age Expansion and distortion may occur with skin stretching (e.g., weight gain) Piercings Virtually anywhere on body Ear, nose, lip, tongue, navel most common Rings, studs, posts, chains, "gauges" Trauma and injuries Bruises Extravascular blood from damaged small arteries &/or venules/veins (not capillaries) Exacerbated by &/or clotting disorders (platelet or clotting factor related) Petechiae: Small (1-2 mm) round flat lesions Purpura: Larger (> 3 mm) lesions that do not blanche under pressure; may be raised or firm Ecchymoses: Largest (> 1 cm), flat; usually geographic or irregular shape Abrasions Superficial injury confined to epidermis/ superficial dermis Pressure/crush type Tangential/brush type May bleed or crust depending on depth May occur after death from moving the body Lacerations

: s s p t p t hhtt

rrss e e k k o o o o eebb

Autopsy Fundamentals: Autopsy Performance

INTEGUMENTARY SYSTEM

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m Scleroderma t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

Melanoma Asymmetry Borders (irregular) Color (variegated) Diameter (> 6 mm) Evolving over time (growing, changing) Dermatitis (rash) Intertrigo (intertriginous dermatitis): Inflammatory condition of skin folds; induced by heat, moisture, friction, lack of air circulation Atopic: Eczema, allergy Contact: Poisonous plants and insects, nickel, skin irritants Stasis: Chronic edema Abscess Subcutaneous fluctuant lesions Red, indurated surrounding tissue

Drug sensitivity (sulfonamides, barbiturates, antibiotics) Erythema multiforme minor: Mild manifestation Erythema multiforme major or Stevens-Johnson syndrome: Severe manifestation with blistering

Autoimmune fibrosing skin disease

Localized (morphea) Generalized (systemic sclerosis) Cutaneous findings Localized lesions: Red patches evolve to hypopigmented plaques with dark borders, usually on trunk Sclerodactyly ("sausage" fingers) Taut, thickened facial skin Telangiectasias, hypopigmentation Anti-centromere, Scl-70 antibodies positive

s s r r s s r r e e e e k k k k o o o o o o o o o o b b b b eebb Specimen Handling e e / / e e / / e e Connective Tissue Disorders (Ehlers-Danlos e e m m . . m m t . . / and Pseudoxanthoma Elasticum)://t t t / / / : / / : : ss ss p p t t p p t t t t hht hht Sampling skin at autopsy

Take care to keep skin integrity intact prior to embalming Sampling along "Y" incision lines encouraged when necessary Consider frozen samples for immunofluorescence studies (immunobullous disease, etc.)

Skin laxity

Especially on extensor surfaces on joints

Pseudoxanthoma elasticum

Yellow papules over redundant skin folds on the neck, abdomen, and groin Histologically, elastic fibers become brittle and calcified Associated clinically with hypertension, peripheral vascular and coronary artery disease, retinal and gastrointestinal hemorrhage, and stroke Ehlers-Danlos Multiple (at least 11) types Clinical associations Mitral valve prolapse Blue sclerae Vascular aneurysms, dissections Peripheral vascular disease

s s r r s s r r e e e e k k ook ook o o o o o o b b b b b eeb Genetic Syndromes e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht Disseminated Intravascular Coagulation COMMON DERMATOLOGIC DISEASES AT AUTOPSY

Caf au lait spots: Neurofibromatosis Ash leaf spots (under Wood’s lamp), sebaceous adenoma: Tuberous sclerosis

Prominent nevi: Dysplastic nevus syndrome Port-wine stain: SturgeWeber syndrome

Petechiae, purpura, haemorrhagica bullae Purpura fulminans: Diffuse microvascular clotting in

REPORTING CRITERIA

s s r r s s Tattoos,e Piercings r r e e e k k ookPyoderma Gangrenosum ook o o oo o o b b b Scars b b eeb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / Lesions : : s s s s p p t t p p t t t t hhtt h h SELECTED REFERENCES

superficial subcutaneous vessels Diffuse ecchymoses Bleeding from wounds or venipuncture sites

Pustules or nodules that ulcerate and extend centrifugally

Lower extremities most common Associated with

Rheumatoid arthritis Inflammatory bowel disease Paraproteinemia (multiple myeloma)

Erythema Multiforme/Stevens-Johnson Syndrome

rrss e e k k o o o o eebb

Location, size, nature (photographs helpful) Location, orientation, length, color Contracture, keloid formation Character, location, size 1.

Kovarik CL et al: Forensic dermatopathology and internal disease. J Forensic Sci. 50(1):154-8, 2005 Rutty GN et al: The external examination. In: Hospital Autopsy. 2nd ed. London: Hodder Arnold. 42-51, 2001 Knight B et al: The autopsy: external examination. In: Forensic Pathology. London: Hodder Arnold. 12-17, 1996 Knight B et al: The pathology of wounds. In: Forensic Pathology. Arnold. London: Hodder Arnold. 133-70, 1996

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

Cutaneous hypersensitivity reaction

Macules, papules, plaques, vesicles, or bullae Often with targetoid or iris appearance Acral distribution (extremities) Associated with Infection (herpes simplex virus or Mycoplasma)

2. 3. 4.

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt INTEGUMENTARY SYSTEM

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

Clinical Features

(Left) This image shows massive ecchymoses surrounding a femoral cannulation site used for a temporary extracorporeal circulatory circuit prior to the death of this patient. She had developed a significant coagulopathy. (Right) This image shows dressed from an recent incisions endoscopic vein harvesting procedure. The veins were used in coronary artery bypass grafting. There is significant bruising along the harvesting tract .

(Left) Multiple actinic keratoses are seen on the scalp of this patient. There is discoloration and prominent crusting. The texture is described as rough, like sandpaper. (DP: Neoplastic Derm.) (Right) Numerous cutaneous neurofibromas may be seen in a diffuse distribution in patients with neurofibromatosis. They are characterized by sessile or pedunculated fibrous growths. A single caf au lait spot is also present . (From DP: Familial Cancer.)

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

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rrss e e k k o o o o eebbI

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

(Left) This image shows the typical appearance of facial angiofibromas seen in tuberous sclerosis. These often appear before puberty and start in the nasolabial fold. They can be numerous and extensive on the face and scalp. (From DI: Obstetrics, 2e.) (Right) These portwine stains involving the distribution of the trigeminal nerve may be an external sign of Sturge-Weber syndrome. (From DP: Neoplastic Derm.)

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: s s p t p t hhtt

: s s p t p t hhtt Autopsy Fundamentals: Autopsy Performance

INTEGUMENTARY SYSTEM

rrss Features rrss Microscopic e e e e k k k k o o o o o o o o o o b b b b eebb e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o eebb

(Left) This histologic section of a basal cell carcinoma shows a proliferation of small, infiltrative nests of basaloid cells with prominent retraction artifact in a somewhat scleroticappearing stroma. (From DP: Neoplastic Derm.) (Right) This seborrheic keratosis with a papillary appearance shows hyperkeratosis , papillomatosis, acanthosis, and horn cysts/pseudocysts . A fibrovascular stalk may be present in some cases. (From DP: Neoplastic Derm.)

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht (Left) Features of pyoderma gangrenosum are present in this skin section, with undermining of the epidermis by numerous neutrophils and epidermal ulceration . (From DP: Nonneoplastic Derm.) (Right) This skin sample from a patient with erythema multiforme shows scattered necrotic (apoptotic) keratinocytes and subepidermal bulla formation . (From DP: Nonneoplastic Pediatrics.)

s r s r e e k ook o o b eeb

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hht hht

s r s r e e k ook o o b eeb

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

rrss e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e I m m . . m m t t . . / / t t / / / / : : / / : : s s 2 s s tp tp hhtttp hhtttp

(Left) This skin sample from a patient with systemic sclerosis (scleroderma) shows abundant dermal fibrosis , extending to involve adnexal structures at the junction between the cutis and subcutis. (From DP: Nonneoplastic Derm.) (Right) This high-magnification photomicrograph from a skin section from a patient with pseudoxanthoma elasticum shows calcified elastic fibers (von Kossa stain). (From DP: Nonneoplastic Derm.)

Autopsy Fundamentals: Autopsy Performance

: s s p t p t hhtt

: s s p t p t hhtt ORAL CAVITY

rrss e e k k o o o o eebb

s r s r e e k k o o o o eebb

rrss e e k k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht

s r s r e e k k o o o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / : : ss ss p p t t p p t t t t hhtCAVITY DISEASE hht PRIMARY ORAL Erythroplakia This tongue demonstrates extensive loss of papillae. This is atrophic glossitis that may be associated with nutritional deficiencies such as B12 deficiency. (Courtesy R. Irvine, MD.)

Caries (Tooth Decay, Cavities)

Bacterial infection of the mouth that causes

s r s r e e k ook o o b eeb Periodontitis

Chronic, inflammatory process in the mouth affecting gingiva and other periodontal tissues (alveolar bone, periodontal ligament, and cementum) that causes loosening of the teeth and tooth loss Related to excess of plaque: Biofilm normally found in the mouth May also be a source for systemic infection, including infective endocarditis May risk for coronary artery disease and ischemic heart disease Gingival enlargement with periodontitis may be manifestation of monocytic leukemia, consider sampling tissue

Leukoplakia

to another entity (e.g., candidiasis, etc.) Most often on buccal mucosa, floor of mouth, palate, gingiva, ventral tongue White, often well-demarcated plaques that may be smooth or thick and even corrugated Histology: Hyperkeratotic mucosa with acanthosis (thickening) Premalignant lesion more commonly seen in the mouths of smokers and chewing tobacco users May see a range of atypia dysplasia carcinoma in situ

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another disease entity Flat or depressed, occasionally with erosion Commonly with dysplasia carcinoma in situ invasive carcinoma Submucosal inflammatory infiltrate with dilated vessels erythematous appearance Smoking and alcohol are risk factors; 2:1 male predominance

Examination of oral cavity to exclude malignancy,

particularly in decedents with history of tobacco use is mandatory Squamous cell carcinoma is most common oral cavity malignancy Ventral tongue, floor of mouth, lower lip, soft palate, and gingiva are common locations Early plague-like or verrucous lesions progress to ulcerated masses with indurated and rolled edges Carcinoma in situ invasion Varying degrees of differentiation from welldifferentiated keratinizing lesions to sarcomatoid tumors If invasion is suspected, cervical node sampling should be considered on ipsilateral side of neck (with family permission)

s r s r e e k ook o oo o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / : : s s s s p p t t p p t t hhtt hhtt

White plaque in the mouth that cannot be attributed

rrss e e k k o o o o eebbI

Red area in the mouth that cannot be attributed to

s r s r e e k ook o o o o b b b b e e / / e e / / e e e e m m . . m m t t . . / / t t / / / / : : / / Oral Squamous Cell Carcinoma : : ss ss p p t t p p t t t t hht hht

breakdown of hard substances of tooth (enamel, dentin, and cementin) May be a source for systemic infection, including infective endocarditis

s r s r e e k ook o o b eeb

This strawberry tongue has hypertrophy of the tongue papillae . This may be seen in scarlet fever, Kawasaki disease, and toxic shock syndrome. (Courtesy R. Irvine, MD.)

ORAL CAVITY MANIFESTATIONS OF SYSTEMIC DISEASE

ss r r e e k Angular Cheilitis k o o o o o o b b b b e e / / e e / / e e e e m m .t.m .t.m t t / / / / / / : : / / ss: ss: p p t t p p t t t t hht hht Inflammation at 1 or more commonly both lip commissures (nutritional deficiency)

: s s p t p t hhtt

rrss Glossitis e e k k o o o o eebb

Autopsy Fundamentals: Autopsy Performance

ORAL CAVITY

Similar to FAR in structure and content

Comment section

Narrative summary of initial findings and remaining questions Statement of preliminary nature of report Include contact information for follow-up questions, obtaining final report May include expected timeline for FAR release

SELECTED REFERENCES 1.

2. 3. 4.

Finkbeiner WF et al: The autopsy report. Autopsy Pathology: A Manual and Atlas. 2nd ed. Philadelphia: Saunders-Elsevier. 123-9, 2009 Adams VI: Guidelines for Reports by Autopsy Pathologists. New York City: Humana Press, 2008 Sheaff MT et al: Post Mortem Technique Handbook. 2nd ed. New York City: Springer. 338-49, 2005 Hanzlik RL et al: The autopsy lexicon: suggested headings for the autopsy report. In Collins KA et al: Autopsy Performance and Reporting. 2nd ed. Northfield, IL: College of American Pathologists. 275-85, 2003 Hutchins GM et al: autopsy reporting. In Collins KA et al: Autopsy Performance and Reporting. 2nd ed. Northfield, IL: College of American Pathologists. 265-74, 2003

Autopsy Fundamentals: Autopsy Consent and Reporting

AUTOPSY REPORT

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Autopsy Fundamentals: Autopsy Consent and Reporting

PRESENTING AUTOPSY FINDINGS

A dedicated photographic stand in the morgue facilitates the acquisition of high-quality images and encourages photographic documentation.

Clinicians often cite delay in autopsy diagnosis as

DAY OF AUTOPSY General Comments

Despite the availability of printed and digital teaching resources, there is no more effective way to correlate clinical findings and demonstrate pathologic changes than a properly performed complete autopsy

Involving Clinical Care Team

Contact clinician(s) prior to performance of autopsy

Can provide valuable clinical information to supplement your chart review Can clarify specific questions that clinicians or family may have Provides opportunity to invite interested clinicians to autopsy Scheduling may be difficult and autopsy and release of body should not be unduly delayed Invite interested medical students to view autopsy If clinicians cannot attend autopsy, consider contacting them directly afterwards Especially important if autopsy reveals significant unexpected findings

DAY FOLLOWING AUTOPSY General Comments

Interest of clinical team is often at its peak immediately following death of patient Use the opportunity to interact with clinical team Delays in communicating results or careless presentation of results may discourage future requests for autopsy

Preliminary Anatomic Diagnosis (PAD)

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A well-composed autopsy photograph will show the organ and finding of interest on a clean background that is free of instruments and blood. It is very helpful to include the scale.

Complete PAD within 24 hours whenever possible

48 hours if selected sections have been submitted for histology

shortcoming of hospital autopsies Clinical team may have rotated off of service by the time final diagnosis is complete Prompt PAD helps maintain interest More complete and comprehensive PADs will have greater impact Consider including frozen sections, cytology, or selected sections for rush histology as part of autopsy

Presentation of Fixed Dissected Organs

Be aware of limitations of autopsy permit and of local policy regarding retention of tissue Family wishes or local regulations may prohibit retention of tissue for teaching purposes Present organs only if it does not violate family wishes or local regulations Organs can be presented to clinicians or pathologists/ pathology residents Consider inviting clinical care team to review organs May be easier to schedule than attendance at actual autopsy Consider using organ presentation as way to teach gross pathology to residents Carefully dissected organs should be thoroughly rinsed in cold water If time permits, trim excess fat and extraneous tissues left from day of autopsy Organs should be reasonably free of formalin odor Several shallow metal pans should be lined with moistened white paper towels Organs should be arranged in way that makes anatomic/clinical sense e.g., thoracic organs on one pan, abdominal organs on a second, genitourinary tract on a third Only a representative section or two of grossly normal liver, spleen should be included

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Only representative segments of grossly normal small and large intestine should be included Include demonstrations of all gross abnormalities mentioned in PAD Cover organs with moistened paper towels Encourage member of clinical team to present brief history Uncover organs and present findings Presentation of gross organs increasingly rare Largely supplanted by presentation of photographs

AUTOPSY PHOTOGRAPHY General Comments

Recording images is important part of documenting significant findings Images will be indispensable if findings are to be presented in conference In some cases, images may prove useful as part of future lectures or publications

Equipment

Ideal: Dedicated photographic stand in morgue with adjustable dual lighting sources and dedicated camera In practice, this may not be practical If photographic stand unavailable, any good quality digital camera will suffice

Discuss your findings Get sense of time allotted for your presentation Prepare your images Add labels, arrows, or other indicators to highlight key findings

Presentation

Present gross and then microscopic images Know your audience: Often most are not pathologists Adapt your comments Do not simply give diagnosis, explain features that allow for diagnosis e.g., "acute inflammatory infiltrate in airspaces consistent with pneumonia" rather than "shows pneumonia" Be sensitive to relationship care team had with deceased Keep comments professional Avoid accusations, assignments of blame Invite discussion and questions

After Presentation

Remember to document case presentation in autopsy case file

SELECTED REFERENCES 1.

Composing Images

Rinse away blood and mucus Background should be clean and free of extraneous

fluids, tools, etc.

Orient tissue in a way that makes anatomical sense Include scale to indicate size when possible Take several images Overall (panoramic) image of organ Close up of area of interest Intact organ Cut surface

Autopsy Fundamentals: Autopsy Consent and Reporting

PRESENTING AUTOPSY FINDINGS

Zampieri F et al: The clinico-pathological conference, based upon Giovanni Battista Morgagni’s legacy, remains of fundamental importance even in the era of the vanishing autopsy. Virchows Arch. Epub ahead of print, 2015 Riley RS et al: Digital photography: a primer for pathologists. J Clin Lab Anal. 18(2):91-128, 2004 Belanger AJ et al: Implementation of a practical digital imaging system for routine gross photography in an autopsy environment. Arch Pathol Lab Med. 124(1):160-5, 2000 Edwards WD: Photography of medical specimens: experiences from teaching cardiovascular pathology. Mayo Clin Proc. 63(1):42-57, 1988

INTERDEPARTMENTAL CASE CONFERENCE PRESENTATIONS General Comments

Presentations at interdepartmental meetings provide opportunity to represent your department and your specialty Thank organizers for opportunity to participate Show enthusiasm for case Even cases that seem routine can be instructive

Preparation

Know your role

Main presenter or adjunct to main presentation If adjunct, consider submitting your presentation to presenting clinician beforehand Will allow for incorporation of your presentation into larger presentation Obviates time-consuming transitions Consult with clinicians beforehand Clarify the history

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SECTION 1

Sudden and Unexpected Death

Cardiovascular Pulmonary Thromboembolism

II-1-2

Acute Myocardial Infarction

II-1-4

Cardiomyopathy

II-1-8

Myocarditis

II-1-12

Cardiac Conduction System

II-1-18

Aortic Dissection

II-1-24

Abdominal Aortic Aneurysm

II-1-30

Respiratory Pulmonary Edema

II-1-32

Pulmonary Hemorrhage

II-1-36

Tension Pneumothorax

II-1-40

Gastrointestinal Upper Gastrointestinal Hemorrhage

II-1-44

Lower Gastrointestinal Hemorrhage

II-1-48

Intestinal Ischemia

II-1-52

Hepatobiliary Hepatic Hemorrhage

II-1-56

Hemorrhagic Pancreatitis

II-1-60

Acute Liver Failure

II-1-64

Genitourinary Pregnancy Complications

II-1-68

Acute Renal Failure

II-1-74

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Endocrine 1%`

II-1-84

Adrenocortical Excess

II-1-88

CNS Seizure Disorders

II-1-92

Subdural Hemorrhage

II-1-96

Subarachnoid Hemorrhage

II-1-100

Stroke

II-1-104

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Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY THROMBOEMBOLISM

A large, serpiginous, dark red thromboembolus is present at the bifurcation of the main pulmonary artery (saddle embolus) of this thoracic organ block. Note the cut end of the aorta .

TERMINOLOGY

MACROSCOPIC FEATURES

Abbreviations

External Examination

Pulmonary thromboembolism (PTE)

Deep venous thrombosis

Swollen red lower extremity Bilateral calf and thigh circumference

Synonyms

Venous thromboembolism (VTE)

Internal Examination

Definitions

Embolus: Solid, gaseous, or liquid mass that travels in circulation from its point of origin to distant location (usually an end artery) Thromboembolus: Composed of thrombus material PTE: Thromboemboli in pulmonary arterial circulation, virtually all arising from deep veins of lower extremity

CLINICAL ISSUES Presentation

Wells criteria: Clinical risk score for PTE (0-1 = low, 2-6 = intermediate, > 6 = high) Clinical signs/symptoms of PTE (3) PTE/VTE favored clinical diagnosis (3) Heart rate > 100 (1.5) Surgery/immobilization in last 30 days (1.5) Prior VTE (1) Hemoptysis (1) Active or treated malignancy in last 6 months (1)

Laboratory Tests D dimer elevation

High negative predictive value Nonspecific Postmortem utility not proven

Alternating areas rich in fibrin and platelets and red (lines of Zahn) in a thromboembolus blood cells indicate that it arose from a thrombus that formed in flowing blood (i.e., antemortem).

Often unremarkable or findings related to trauma, recent surgery, underlying malignancy

After incising iliac veins, lower extremities elevated and "milked" Free-flowing blood from iliacs = no obstruction

Organ Examination Cardiovascular system

Remove heart and lung block together to avoid disruption of pulmonary thromboembolus Open pulmonary artery along anterior aspect of bifurcation Check for PTE proximally ("saddle") or distally Thromboembolus has shape of vessel of origin, has venous valve markings Right ventricular dilatation, thromboembolus in transit Patent foramen ovale (potential for paradoxical embolization) IVC filter (postmortem radiograph helpful) Respiratory system Pulmonary vasculature opened completely to identify PTE (may be multiple) Webs within pulmonary artery indicate organized and recanalized thromboemboli Pulmonary edema may indicate preexistent congestive heart failure, a contributory cause of PTE Hepatobiliary system Liver congestion from acute cor pulmonale Malignancy: Occult tumor

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Key Facts Terminology

Thromboemboli in pulmonary arterial circulation, virtually all arising from deep veins of lower extremity

Macroscopic Pathology

Signs of deep venous thrombosis include swollen red lower extremity; measure bilateral calf circumference to reveal subtle swelling

Risk factors: Recent surgery, hip fracture, atrophy of lower extremities suggesting paralysis, trauma

Remove heart and lung block together to avoid disruption of pulmonary thromboembolus, open pulmonary artery anteriorly Check for presence of thromboembolus either proximal within bifurcation (saddle embolus) or distal vasculature True thromboembolus has shape of vessel of origin, has venous valve markings on exterior

MICROSCOPIC PATHOLOGY

REPORTING CRITERIA

Histologic Features

Presence and Location of Thromboembolus

Thromboembolus

Recent Red blood cells layered with fibrin and platelets (lines of Zahn) May be subtle, thin, peripheral Organizing Cellular infiltration (macrophages and neovessels) Starting at edges and progressing inward Lung Congestion edema Infarction: Coagulative necrosis with hemorrhage (red infarct) Hepatobiliary Centrilobular congestion necrosis Malignancy Tumor emboli

Cause of death or contributor? Underlying risk factors identified from chart review or postmortem

SELECTED REFERENCES 1.

Tadlock MD et al: The origin of fatal pulmonary emboli: a postmortem analysis of 500 deaths from pulmonary embolism in trauma, surgical, and medical patients. Am J Surg. Epub ahead of print, 2014 Anderson FA Jr et al: Risk factors for venous thromboembolism. Circulation. 107(23 Suppl 1):I9-16, 2003 Wells PS et al: Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med. 129(12):997-1005, 1998 Lindblad B et al: Autopsy-verified pulmonary embolism in a surgical department: analysis of the period from 1951 to 1988. Br J Surg. 78(7):849-52, 1991

Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY THROMBOEMBOLISM

DIFFERENTIAL DIAGNOSIS Postmortem Blood Clot

"Chicken fat" (yellow gelatinous) "Currant jelly" (dark red) Random arrangement of coagulated serum and red blood cells

Not adherent to wall

IMAGE GALLERY

II (Left) These venous thromboemboli were removed from a pulmonary artery at autopsy. Their shape is a cast of the vein in which they formed. They are often coiled . (Center) This lung contains multiple wedge-shaped hemorrhagic pulmonary infarcts . The wedge base is located at the pleura. Lower lobe infarcts are most common. (Right) Pulmonary infarcts are hemorrhagic and show coagulative necrosis of the alveolar http://basicbook.net septa and vessels .

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE MYOCARDIAL INFARCTION

Recent transmural posterior/inferior wall myocardial infarction is seen in this gross photograph with a marbled tan-red appearance and gross softening.

TERMINOLOGY

CLINICAL ISSUES

Synonyms

Epidemiology

Myocardial ischemia, heart attack, acute coronary syndrome

Definitions

Myocardial infarction can be defined as irreversible myocardial muscle damage caused by prolonged ischemia, resulting from sustained imbalance of perfusion, supply, and demand

ETIOLOGY/PATHOGENESIS Coronary Artery Atherosclerosis Risk Factors Smoking Hypertension Elevated low-density lipoprotein cholesterol Diabetes Increasing age

Nonatherosclerotic Coronary Disease

Coronary artery vasculitis Coronary artery amyloidosis Coronary artery dissection Coronary artery spasm Coronary artery embolus (such as from endocarditis)

Other Causes of Mismatched Perfusion and Myocardial Demand Left ventricular hypertrophy (cardiomyopathy, hypertensive heart disease)

Congenital heart disease Cardiac arrest (from nonischemic causes) Metabolic, neurogenic, arrhythmia

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Photomicrograph shows a coronary artery with recent thrombus occluding the lumen.

Impaired oxygen delivery (respiratory failure, severe anemia)

Incidence

Annual incidence of new myocardial infarction in USA has been estimated at 610,000 cases Recurrent myocardial infarction accounts for 325,000 additional episodes Age Average: 64.5 years for men and 70.3 years for women Gender M>F Women thought to be "protected" from coronary atherosclerosis in their reproductive years Ethnicity Prevalence is highest in developed nations, presumably due to comparatively high-calorie diet, more sedentary lifestyle, and longer life expectancy Significant variation in incidence across developed nations, with rates (per 100,000) such as 30 in Japan 39.8 in France 65.2 in Italy 94.9 in Canada 106.5 in United States 216 in Slovakia

Presentation

Cardiac arrest without recognized antecedent symptoms

Typical symptoms

Chest pain (angina) on exertion or rest Mandibular, upper arm, or epigastric discomfort; usually lasts > 20 minutes Associated nausea, diaphoresis, syncope No symptoms In elderly, women, diabetic, postoperative, and critically ill

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Key Facts

7-10 days: Grossly softened and depressed with more

Terminology

Irreversible myocardial damage caused by prolonged ischemia, resulting from sustained imbalance of perfusion, supply, and demand

prominent hyperemic edges

3-8 weeks: Grayish-white scar begins to form at edges and progresses to center

Clinical Issues

Microscopic Pathology

Rupture of myocardium (tamponade, acquired ventricular septal defect, ruptured papillary muscle) Complications: Long term Ischemic dilated cardiomyopathy Ventricular true aneurysms (often with mural thrombus)

contraction bands, and heavy neutrophilic infiltration 3-7 days: Myocyte loss, karyorrhexis of neutrophils ("nuclear dust"), early phagocytosis by macrophages at infarct border 10-14 days: Well-established granulation tissue with new blood vessels and fibroblast infiltration 2-8 weeks: Increased collagen deposition with decreased cellularity

Complications: Acute

Macroscopic Pathology

12-24 hours: No changes or subtle mottling

1-3 days: Coagulative necrosis with loss of nuclei,

Treatment

IMAGE FINDINGS

Coronary artery bypass grafting Percutaneous coronary intervention (PCI) Usually reserved for acute ST elevation myocardial infarction (salvageable myocardium) Balloon angioplasty with coronary artery stenting Drugs Sublingual nitroglycerin Antiplatelet therapy (aspirin, clopidogrel) Morphine for pain relief Thrombolytic agents (effective only in 1st hours after acute coronary thrombosis) 1st generation: Streptokinase, urokinase, acetylated plasminogen streptokinase activator complex (APSAC) 2nd generation: t-PA, tenecteplase

MR Findings

Surgical approaches

Prognosis

Median 30-day mortality: 16.6% Median 30-day readmission: 19.9% Complications

Accurate assessment of myocardial function and motion and perfusion (with contrast)

Echocardiography

Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE MYOCARDIAL INFARCTION

Assesses myocardial thickness and motion Assesses myocardial perfusion and microvascular obstruction (coronary flow reserve)

Radionucleotide Imaging

Commonly used to assess perfusion and viability

MACROSCOPIC FEATURES General Features

In initial few minutes to hours (up to 8-12 hours), there is no grossly apparent abnormality

Thereafter

Acute Cardiogenic shock Rupture of myocardium (tamponade, acquired ventricular septal defect, ruptured papillary muscle) Ventricular pseudoaneurysm (contained rupture) Pericarditis (Dressler syndrome) Arrhythmias Sudden death Longer term Congestive heart failure Ischemic dilated cardiomyopathy Ventricular true aneurysms (often with mural thrombus) Mitral regurgitation (scar retraction of papillary muscle) Recurrent ventricular arrhythmias Risk of 2nd myocardial infarction

12-24 hours: No change or subtle mottling and regional stiffness 1-3 days: Mottling with yellow-tan center 3-7 days: Yellow-tan center with hyperemic edges 7-10 days: Grossly softened and depressed with more prominent hyperemic edges 10-14 days: Edges become more gray in color 3-8 weeks: Grayish-white scar begins to form at edges and progresses to center 8-12 weeks: Grayish-white scar with early remodeling (wall thinning and chamber dilatation)

Hemorrhagic Infarct

After revascularization (durable or failed), restoration of blood flow to damaged tissue may result in hemorrhagic infarction Dark red-brown in color due to hemorrhage into ischemic tissues

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE MYOCARDIAL INFARCTION Vital Staining of Fresh Heart Tissue (Autopsy) Triphenyltetrazolium chloride (TTC) or nitro blue

tetrazolium (NBT) dye test Redox indicator catalyzed by dehydrogenase enzymes in viable myocardium (but not infarcted myocardium) TTC will stain viable myocardium brick red (infarcted myocardium will remain unchanged) NBT will stain viable myocardium dark blue-purple (infarcted myocardium will remain unchanged)

MICROSCOPIC PATHOLOGY

DIFFERENTIAL DIAGNOSIS Chest Pain

Clinically, can be due to

Acute aortic dissection Pericarditis Gastrointestinal disorders (reflux, cholecystitis, gastritis) Pneumonia Pulmonary embolism Pneumothorax

SELECTED REFERENCES

Histologic Features

After 4 hours (variable), myocytes may appear wavy and elongated, interstitial edema

Within 24 hours, interstitial edema, focal hemorrhage, myocyte contraction bands, and infiltration of neutrophils (margination) Staining for C4d may be positive in acutely ischemic myocytes due to complement activation 1-3 days: Coagulative necrosis with loss of nuclei, contraction bands, and heavy neutrophilic infiltration 3-7 days: Myocyte loss, karyorrhexis of neutrophils ("nuclear dust"), early phagocytosis by macrophages at infarct border 7-10 days: Well-developed phagocytosis with distended macrophages, granulation tissue at infarct border 10-14 days: Well-established granulation tissue with new blood vessels and fibroblast infiltration 2-8 weeks: Increased collagen deposition with decreased cellularity > 2 months: Dense collagenous scar Caveat: This sequence of changes assumes no revascularization (no reversal of ischemia) Spontaneous or interventional reperfusion must be taken into account Reperfusion injury (after revascularization) Prominent coagulative necrosis Marked erythrocyte extravasation/hemorrhage Small vessels may show small thrombi or atheroemboli

Chang J et al: Pathology of myocardial infarction. Diagnostic Histopathology. 19(1):7-12, 2013 2. Hoyert DL et al: Deaths: preliminary data for 2011. Natl Vital Stat Rep. 61(6):1-51, 2012 3. Hamm CW et al: ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 32(23):2999-3054, 2011 4. Jenkins CP et al: The utility of C4d, C9, and troponin T immunohistochemistry in acute myocardial infarction. Arch Pathol Lab Med. 134(2):256-63, 2010 5. Krumholz HM et al: Patterns of hospital performance in acute myocardial infarction and heart failure 30day mortality and readmission. Circ Cardiovasc Qual Outcomes. 2(5):407-13, 2009 6. Antman EM et al: ST-elevation myocardial infarction: Pathology, pathophysiology, and clinical features. In Libby P et al: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: Saunders Elsevier. 1207-32, 2008 7. Kung HC et al: Deaths: final data for 2005. Natl Vital Stat Rep. 56(10):1-120, 2008 8. Thygesen K et al: Universal definition of myocardial infarction. Eur Heart J. 28(20):2525-38, 2007 9. Pasotti M et al: The pathology of myocardial infarction in the pre- and post-interventional era. Heart. 92(11):1552-6, 2006 10. Olsen EGJ: Myocardial infarction. In The Pathology of the Heart. 2nd ed. Basingstoke and London: Macmillan Press. 99-132, 1980

ANCILLARY TESTS Immunohistochemistry

C4d, C9: Positive staining in necrotic myocardium cTnT: Negative staining in necrotic myocardium

Electron Microscopy Transmission

Sarcolemmal disruption Mitochondrial swelling, mitochondrial amorphous densities Relaxation of myofibrils Glycogen loss

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Gross and Microscopic Features (Left) This left anterior descending artery shows recent thrombus occluding the lumen. This artery supplies the anterolateral wall of the left ventricle. (Right) This gross photograph shows an aneurysm involving the apex of the left ventricle. The aneurysms are seen more frequently in healed transmural infarct than subendocardial infarct. A is seen in the thrombus cavity of the aneurysm. (Courtesy J. Fernandes, MD.)

(Left) Acute myocardial infarction that is 24-48 hours old shows anuclear hypereosinophilic myocytes and acute inflammatory infiltrate . (Right) Healing infarct that is 2 weeks old shows necrotic myocytes in the center, surrounded by granulation tissue composed of fibroblasts, chronic inflammation, and neocapillaries.

Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE MYOCARDIAL INFARCTION

(Left) Acute reperfusion infarct shows anuclear hypereosinophilic myocytes , hemorrhage , and neutrophils . Reperfusion infarcts are usually hemorrhagic and can be extensive. (Right) Photomicrograph shows a well-healed transmural infarct. There is dense fibrosis with focal fatty infiltration.

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Organ System Approach to Autopsy: Sudden and Unexpected Death

CARDIOMYOPATHY

This autopsy heart specimen from a patient with multiple interventions (bypass grafts , epicardial leads , ) poses a and left ventricular assist device conduits challenge for cardiomyopathy evaluation.

TERMINOLOGY Definitions

Cardiomyopathies are a complex set of disorders often posing diagnostic challenges

This chapter outlines a systematic approach to cardiomyopathies, primarily on basis of gross pathologic features

Amyloidosis

Etiology Primary Secondary Alcoholic Peripartum

Morphology

Dilated Hypertrophic Restrictive

Physiology

Systolic heart failure Diastolic: Preserved ejection fraction heart failure

AMERICAN HEART ASSOCIATION CLASSIFICATION (2006) Primary

Genetic

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Stress provoked (Takotsubo/apical ballooning) Tachycardia induced Peripartum Mixed Dilated cardiomyopathy Primary restrictive cardiomyopathy

Secondary

BASES FOR CLASSIFICATION

This 4 chamber long axis view of a heart at autopsy shows ischemic cardiomyopathy features with ventricular aneurysm . Pacemaker leads , and an LVAD inflow cannula is also seen.

Hypertrophic cardiomyopathy Arrhythmogenic cardiomyopathy Left ventricular noncompaction/hypertrabeculation Mitochondrial myopathies Ion channel disorders Acquired Inflammatory (myocarditis)

Primary (AL, AH) Senile (ATTR) Familial (numerous) Other infiltrative disease Gaucher Hurler Hunter Storage disease Fabry Hemochromatosis Eosinophilic endomyocardial disease Sarcoidosis Endocrine Diabetic cardiomyopathy Thyroid dysfunction (hyper or hypo) Cardiofacial Noonan syndrome Lentiginosis Neuromuscular Friedrich ataxia Muscular dystrophy Nutritional Beriberi Pellagra Autoimmune/collagen vascular Lupus Rheumatoid Electrolyte imbalance Consequence of cancer therapy Radiation induced

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Anthracycline toxicity

MICROSCOPIC FINDINGS Histologic Features

MACROSCOPIC FINDINGS

Interstitial fibrosis Myocyte hypertrophy

External Examination

Lower extremity edema Ascites (abdominal distension) Pacemaker, implanted defibrillator Ventricular assist device

Internal Examination Cardiothoracic ratio

Heart:chest diameter in situ

Pulmonary edema and congestion Pleural effusions

Liver enlargement (early) or "cardiac cirrhosis" (late) Nephrosclerosis Possible indicator of hypertensive heart disease

Organ Examination

Left ventricular hypertrophy

Heart weight > 150-175% of expected weight = moderate to severe hypertrophy Ratio of septal:free wall thickness > 1.3 = asymmetric septal hypertrophy Exclude papillary muscles when measuring free wall Left ventricle dilatation Short axis left ventricle internal diameter > 5 cm = severely dilated Other chambers usually enlarged due to congestion from systolic failure Dilated cardiomyopathy shows both dilatation and hypertrophy (by heart weight criteria) Right-sided effects Pulmonary venous hypertension Secondary to elevated left atrial pressure/ congestion Dilated and tortuous vein branches in lobular septa Septal edema and widening, prominent septal lymphatics Intraalveolar hemosiderophages (heart failure cells) Right ventricle enlargement Complex chamber geometry precludes criteria for dilatation using width "Gestalt" sense more useful Right ventricle thickness (excluding trabeculation) > 0.6 = hypertrophy

Ventricular Assist Devices and Other Hardware

Evaluate for pump thrombus, position and patency of cannulas

Evaluate anastomotic connections for kinking, bending, extrinsic compression

Deactivate implantable defibrillators

Coordinate with pacemaker nurse for institution, manufacturer Potential for electric shock to autopsy personnel

Binucleation of myocytes (mild, early) Enlarged, hyperchromatic "boxcar" nuclei (moderate, severe) Primary cardiomyopathy is a diagnosis of exclusion; must rule out the following Chronic valvular disease Hypertensive heart disease Ischemic heart disease Etiology specific findings Myocyte disarray: Hypertrophic cardiomyopathy Hemosiderin: Hemochromatosis Amyloid: Amyloidosis Marked transmural myocyte vacuolization: Storage disease Foamy macrophages: Gaucher

COMMON CARDIOMYOPATHIES Idiopathic Dilated Cardiomyopathy Features

Moderate-severe LV dilatation (LVISD > 4 cm) Moderate-severe LV hypertrophy (heart weight > 150% of expected weight) Myocyte hypertrophy and interstitial fibrosis Etiology Presumed to be late post myocarditis (viral or post viral) in most cases Termed "idiopathic" due to lack of definitive causation Wide age range (congenital to elderly) Rare forms: Familial, alcoholic, peripartum, hemochromatosis, tachycardia induced Differential diagnosis Mainly valvular disease, regurgitant valves (volume hypertrophy)

Organ System Approach to Autopsy: Sudden and Unexpected Death

CARDIOMYOPATHY

Hypertrophic Cardiomyopathy Features

Thick left ventricle walls, especially septum (septum to free wall ratio > 1.3) Small left ventricle chamber volume Moderate to severe LVH (heart weight > 150% of expected) Myocyte hypertrophy, interstitial fibrosis, myocyte disarray Left atrium and right chambers also enlarged Etiology Mutations in sarcomeric or sarcomere-associated genes Genetic testing for MYH7, MBPC, others May manifest at any age Common cause of sudden death in young people Differential diagnosis Hypertensive heart disease Aortic stenosis (pressure hypertrophy) Storage disease (LAMP2-Danon)

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Organ System Approach to Autopsy: Sudden and Unexpected Death

CARDIOMYOPATHY Athlete’s heart

Autopsy Considerations

In cases of cardiomyopathy with potential heritability,

Restrictive Cardiomyopathy Features

Normal heart weight or mild hypertrophy (< 150% of expected heart weight) Left atrial enlargement with normal-sized left ventricle and normal valves Right chambers may be enlarged chronically Etiology Primary: Mid to late adulthood, possible association with troponin I mutations Secondary: Infiltrative, storage disease Differential diagnosis Mitral stenosis Constrictive pericarditis Eosinophilic endomyocardial disease

Arrhythmogenic Cardiomyopathy

consider storing frozen samples Blood, myocardium, spleen

REPORTING CRITERIA Gross Examination

Accurate heart weight (great vessels, pericardium, blood removed)

Accurate wall thickness (mid ventricle, exclude papillary muscles)

Left ventricle internal short axis diameter

Microscopic Examination

Degree and extent of fibrosis, hypertrophy Special stains to exclude iron, amyloid, glycogen storage disease, etc.

Features

Often normal heart weight, only mild dilatation (right or left ventricle) Fibrofatty transmural replacement of ventricular wall Diverticular outpouchings from ventricles in areas of wall thinning Right > left ventricle involvement F > M, young adults Etiology Viral and genetic factors are implicated in pathogenesis (possibly complex interaction of environment and genetic predisposition) Screening for cell junction protein defects (desmoplakin, plakoglobin, plakophilin) by immunofluorescence Monomorphic ventricular tachycardia on EKG Sudden cardiac death in young patients Differential diagnosis Normal mural fat, especially in right ventricle wall Fatty degeneration/replacement of myocardium in dilated cardiomyopathy

Disarray in hypertrophic cardiomyopathy Severe myocyte vacuolization in storage disease

SELECTED REFERENCES 1.

3. 4.

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features

Exclude valvular, ischemic, and hypertensive heart disease

Correlate with antemortem imaging (echocardiogram), EKG Systolic or diastolic (preserved ejection fraction) failure Chamber dilatation, enlargement Wall thickness High or low voltage EKG

Rapezzi C et al: Diagnostic work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 34(19):1448-58, 2013 Asimaki A et al: The role of endomyocardial biopsy in ARVC: looking beyond histology in search of new diagnostic markers. J Cardiovasc Electrophysiol. 22(1):111-7, 2011 Basso C et al: Pathophysiology of arrhythmogenic cardiomyopathy. Nat Rev Cardiol. 9(4):223-33, 2011 Maron BJ et al: How should hypertrophic cardiomyopathy be classified?: What’s in a name? Dilemmas in nomenclature characterizing hypertrophic cardiomyopathy and left ventricular hypertrophy. Circ Cardiovasc Genet. 2(1):81-5; discussion 86, 2009 McLeod CJ et al: Histologic characterization of hypertrophic cardiomyopathy with and without myofilament mutations. Am Heart J. 158(5):799-805, 2009 Maron BJ et al: Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 113(14):1807-16, 2006 Lamke GT et al: Surgical pathology of subaortic septal myectomy associated with hypertrophic cardiomyopathy. A study of 204 cases (1996-2000). Cardiovasc Pathol. 12(3):149-58, 2003

Pathologic Interpretation Pearls

Special stains for fibrosis, glycogen, iron, and amyloid Selection can be guided by H&E appearance

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Autopsy examination approximates end systolic dimensions in clinical imaging Rigor causes near maximal ventricular contraction Subject to decomposition changes

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Gross and Microscopic Features (Left) This short-axis view of the ventricles demonstrates features of dilated cardiomyopathy. The internal short-axis diameter is ~ 5 cm. No regional ischemic changes are noted. The right ventricle is normal in size and shows fibrosis surrounding a pacemaker lead tract . (Right) This short-axis section of the ventricles shows ischemic cardiomyopathy with massive transmural infarction of the anteroseptal wall with global left ventricle remodeling (dilatation and wall thinning).

(Left) The conventional regions or "segments" assessed by echocardiography have been superimposed on these short-axis views of the ventricles. Yellow = LAD territory, blue = LCX, and red = RCA (assuming right dominance). (Right) This autopsy heart shows hypertrophic cardiomyopathy. The left ventricle walls are thickened, and both atria are markedly dilated (diastolic failure). An incidental thrombotic-type vegetation is also seen .

(Left) This short-axis view of the left ventricle shows an unusual pattern. Besides left ventricular dilatation, there are features of hypertrabeculation/ noncompaction and fibrofatty infiltration of the left ventricle myocardium . Not all cardiomyopathies are readily classified by morphology. (Right) This photomicrograph shows the typical features common to nearly all cardiomyopathies. The nuclei show features of myocyte hypertrophy , and interstitial fibrosis is also seen.

Organ System Approach to Autopsy: Sudden and Unexpected Death

CARDIOMYOPATHY

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Organ System Approach to Autopsy: Sudden and Unexpected Death

MYOCARDITIS

The definitive features of myocarditis are seen in this high-power image of myocardium, with interstitial and myocyte damage . inflammation

TERMINOLOGY

CLINICAL ISSUES

Definitions

Epidemiology

Inflammatory process involving myocardium with degeneration &/or necrosis of myocytes secondary to infection or autoimmune response

ETIOLOGY/PATHOGENESIS Infectious Agents RNA virus

Coxsackie A and B Influenza A and B DNA virus Adenovirus Herpesviridae (herpes simplex 1 & 2, varicella-zoster, cytomegalovirus [CMV], Epstein-Barr) Poxvirus (variola, vaccinia) Bacteria Gram-positive cocci Rickettsia, Borrelia Fungus Candida Aspergillus Zygomycosis (e.g., Mucor) Parasites Toxoplasma gondii Trypanosoma cruzii (Chagas)

Autoimmune

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This image shows giant cell myocarditis with extensive inflammation, widespread myocyte destruction, and multinucleated giant cells .

Postviral/postinfectious sequela Rheumatic (pancarditis) Giant cell myocarditis Eosinophilic myocarditis Granulomatous myocarditis

Hypersensitivity

Hypersensitivity myocarditis

Incidence

True incidence is unknown Estimated that 10% of acute-onset heart failure is due to acute myocarditis Age Any age, though incidence mirrors viral susceptibility (extremes of age) Gender Slight male predominance

Presentation

New onset of congestive heart failure Atrial/ventricular arrhythmias Embolic events Fatigue Chest pain Palpitations Sinus tachycardia Gallops, murmurs Pericardial friction rub Fever Eosinophilic myocarditis

Absolute eosinophil count > 1.5 x 10/L ANCA to exclude Churg-Strauss

Laboratory Tests

White blood cell count usually elevated Elevated cardiac-specific troponin in 1/3 of cases Elevated creatine kinase isoform MB in 10% of cases Autoantibodies to sarcolemma, alpha myosin, mitochondria, endothelial antigens

Rising IgM/IgG titers to specific virus

Prognosis

Mild cases of myocarditis may be asymptomatic, and patients can recover without sequelae

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Key Facts Etiology

Viral Bacterial Fungal Parasitic Postviral/postinfectious sequela Giant cell myocarditis Eosinophilic myocarditis

Macroscopic Pathology

Pericarditis may also be present (myopericarditis) No gross abnormalities (most common)

Microscopic Pathology Dallas criteria

No myocarditis: No inflammation or myocardial abnormalities

Fulminant myocarditis more likely to have sequelae, but complete recovery is possible after support Progress to dilated cardiomyopathy in ~ 1/3 of cases Sudden death from circulatory failure in acute phase in some cases

IMAGE FINDINGS Radiographic Findings

Cardiomegaly on PA chest radiograph

Ultrasonographic Findings

Myocardium with flabby consistency Mural thrombi in any chamber Pericarditis may also be present (myopericarditis) No gross abnormalities (most common)

Thorough sampling is key 10 full thickness sections from different parts of the ventricles (right, left, apical, mid, basal) Single or rare microscopic foci may incite electrical instability Substrate for sudden cardiac death

MICROSCOPIC PATHOLOGY

Global wall motion decreased Normal diastolic volumes Increased left ventricle wall thickness Right/left ventricular dysfunction

Histologic Features Dallas criteria

MR Findings

Global relative gadolinium enhancement in myocardium compared to skeletal muscle

Increased T2 signal in areas of myocardial inflammation

Delayed enhancement in subepicardial region

EKG

Elevation/depression of ST segment T wave changes Pathologic Q waves Atrial/ventricular arrhythmias

Borderline myocarditis: Inflammatory without myocyte damage Myocarditis: Significant inflammation with myocyte damage Lymphocytic T cells predominate Neutrophils and rare eosinophils may also be seen (mixed) Eosinophilic Prominent interstitial/perivascular eosinophils Eosinophilic granulomas Giant cell Diffuse myocardial infiltration and infarct-like damage No recognizable granulomas Prominent eosinophils in background

Organ System Approach to Autopsy: Sudden and Unexpected Death

MYOCARDITIS

Premature beats Tachycardia Fibrillation Conduction delays

1st diagnostic biopsy No myocarditis: No inflammation or myocardial abnormalities Borderline myocarditis: Sparse inflammatory infiltrate, but damage of myocytes is not demonstrated Myocarditis: Significant inflammation with myocyte damage (necrosis, myocyte vacuolization) 2nd/follow-up biopsy fibrosis Ongoing (persistent) myocarditis: Morphology similar to that in prior biopsy Resolving (healing) myocarditis: Fewer abnormalities than in prior biopsy Resolved (healed) myocarditis: Fibrosis, no inflammation

Lymphocytic/Mixed Myocarditis

MACROSCOPIC FEATURES

T cells predominate Other mononuclear cells present (histiocytes, natural

General Features

Neutrophils and rare eosinophils may also be seen

killer cells, etc.)

Dilatation of left ventricle Cut myocardial surface with markedly variegated mottled appearance with pale foci alternating with minute hemorrhagic lesions

(mixed)

Immunophenotyping not necessary for diagnosis Usually viral/postviral etiology but not specific

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Organ System Approach to Autopsy: Sudden and Unexpected Death

MYOCARDITIS Eosinophilic Myocarditis

Mixed inflammatory cell infiltrate with eosinophils in interstitial or perivascular distribution Eosinophilic granulomas Eosinophil degranulation and breakdown products (Charcot-Leyden crystals) Eosinophil-rich mural thrombus (eosinophilic endomyocardial disease) Careful exclusion of parasitic, fungal infection

Giant Cell Myocarditis

Diffuse myocardial infiltration and infarct-like damage CD8 T cells and histiocytes with singly distributed multinucleated giant cells

No recognizable granulomas Prominent eosinophils in background Individual entrapped cardiomyocytes common

Bacterial Myocarditis

Interstitial infiltrate predominantly composed of neutrophils

Microabscesses may be identified

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features Sudden unexpected death New arrhythmias Recent flu-like illness Unexplained leukocytosis Hypereosinophilia (eosinophilic myocarditis)

Pathologic Interpretation Pearls

Should be considered in absence of other anatomic causes of death

Thorough myocardial sampling when no gross

ANCILLARY TESTS Immunohistochemistry

CD3 staining for T lymphocytes C4d or C9 staining to confirm microscopic foci of myocyte damage

In Situ Hybridization

Viral genomic material demonstrated within myocytes

PCR

Viral genomic material detected in nucleic acid extract

abnormalities seen 10 sections, full thickness, multiple regions of both ventricles Diagnosis requires definite interstitial inflammation and myocyte necrosis or injury Ancillary tests (immunostains, ISH, PCR) not required for diagnosis

SELECTED REFERENCES 1.

from myocardial tissue

Special Stains

Gram GMS/PAS AFB

3. 4.

DIFFERENTIAL DIAGNOSIS Hypersensitivity Myocarditis

History of recent medication use Skin rash, peripheral eosinophilia Eosinophilic myocardial infiltrates

Giant Cell Myocarditis

Mixed myocardial inflammatory infiltrate with presence of giant cells

Extensive areas of myocardial necrosis History of thymoma or autoimmune disorders

Sarcoidosis

7. 8.

Kindermann I et al: Predictors of outcome in patients with suspected myocarditis. Circulation. 2008 Aug 5;118(6):639-48. Epub 2008 Jul 21. Erratum in: Circulation. 118(12): e493, 2008 Calabrese F et al: Myocarditis and inflammatory cardiomyopathy: microbiological and molecular biological aspects. Cardiovasc Res. 60(1):11-25, 2003 Mason JW: Myocarditis and dilated cardiomyopathy: an inflammatory link. Cardiovasc Res. 60(1):5-10, 2003 Calabrese F et al: Molecular diagnosis of myocarditis and dilated cardiomyopathy in children: clinicopathologic features and prognostic implications. Diagn Mol Pathol. 11(4):212-21, 2002 Kawai C: From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation. 99(8):1091-100, 1999 Wojnicz R et al: Immunohistological diagnosis of myocarditis. Potential role of sarcolemmal induction of the MHC and ICAM-1 in the detection of autoimmune mediated myocyte injury. Eur Heart J. 19(10):1564-72, 1998 Aretz HT et al: Myocarditis. A histopathologic definition and classification. Am J Cardiovasc Pathol. 1(1):3-14, 1987 Aretz HT: Myocarditis: the Dallas criteria. Hum Pathol. 18(6):619-24, 1987

Noncaseating granulomas in myocardium, endocardium, or pericardium

Hypercalcemia Lung or other organ involvement

CMV Myocarditis

Viral inclusions identified in endothelial cells CMV DNA detection in myocardial tissue

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MR Findings and Microscopic Features (Left) Cardiac short axis MR shows septal delayed contrast enhancement suggestive of myocarditis. Antemortem findings like this can help guide tissue sampling at autopsy. (Courtesy C. McGann, MD.) (Right) This myocardial section from an autopsy demonstrates sparse mononuclear inflammation in the interstitium; however, no definite myocyte damage is seen. This is at most borderline myocarditis.

(Left) This more fulminant example of lymphocytic myocarditis demonstrates a marked mononuclear inflammatory infiltrate and myocyte damage . (Right) Subacutely, proliferating fibroblasts start to form areas of replacement-type fibrosis in place of the myocytes lost due to myocarditis.

Organ System Approach to Autopsy: Sudden and Unexpected Death

MYOCARDITIS

(Left) This myocardial section demonstrates a predominantly mononuclear inflammatory infiltrate, though rare eosinophils are also present. Lymphocytic myocarditis can demonstrate occasional neutrophils and eosinophils. (Right) Myocyte damage can be subtle and difficult to recognize in some cases. Close inspection on high magnification is needed. This example of lymphocytic myocarditis also includes some eosinophils .

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Organ System Approach to Autopsy: Sudden and Unexpected Death

MYOCARDITIS

Microscopic Features (Left) This intermediatemagnification photomicrograph shows a focus of myocardial inflammation with myocyte destruction and a single multinucleated giant cell , diagnostic of giant cell myocarditis. (Right) This more typical view of giant cell myocarditis shows widespread destruction of myocardium with extensive mixed inflammation and singly distributed giant cells , without granuloma formation. Lymphocytic myocarditis is usually focal; giant cell myocarditis is usually diffuse.

(Left) This example of giant cell myocarditis shows some preserved myocardium but otherwise extensive loss of cardiomyocytes with active myocyte damage . These myocytes are irreversibly injured, and replacement fibrosis will form in this area. (Right) Giant cells may be small and inconspicuous, as seen in this high-magnification photomicrograph. Their presence is nonetheless diagnostic of giant cell myocarditis.

(Left) In the later stages of giant cell myocarditis, extensive replacement fibrosis occurs with only rare islands of preserved (entrapped) myocytes . A single residual giant cell indicates the type of myocarditis in this patient. Giant cell myocarditis is usually temporally uniform but may show more active areas of inflammation along with replacement fibrosis. (Right) This image shows healing/ healed giant cell myocarditis with entrapped preserved cardiomyocytes .

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Microscopic Features (Left) The abundance of eosinophils in this example of myocarditis is suggestive of eosinophilic myocarditis. Other inflammatory cells are present, but eosinophils at least equal the number of any other constituent inflammatory cell. (Right) While no definite myocyte damage is seen in this particular field, damage was present elsewhere. Again, eosinophils are a very prominent component of the inflammatory infiltrate.

(Left) In this case of eosinophilic myocarditis, many of the eosinophils are releasing their cytoplasmic granules (degranulation). These granules contain the enzymes that damage the myocytes. (Right) This autopsy specimen from a patient with eosinophilic endomyocardial disease shows mottling of the myocardium (corresponding to eosinophilic myocarditis microscopically) and an eosinophil-rich mural thrombus in the right ventricle apex .

Organ System Approach to Autopsy: Sudden and Unexpected Death

MYOCARDITIS

(Left) This photomicrograph shows mural thrombus with areas rich in eosinophils and progressive thrombus organization with fresh fibrin thrombus on top. (Right) The eosinophils in this clot are more difficult to recognize since many have degranulated. The characteristic bilobed nucleus can still be seen and is a helpful diagnostic clue to their identity.

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Organ System Approach to Autopsy: Sudden and Unexpected Death

CARDIAC CONDUCTION SYSTEM

This illustration shows the approximate locations of the sinoatrial node (subepicardial), atrioventricular node (subendocardial), and His bundle .

MACROSCOPIC FINDINGS Sinoatrial (SA) Node

Specialized "pacemaker" myocyte collection in right atrium

Subepicardial structure near superior vena cava,

overlying terminal crest (vertical crest on interior wall of right atrium that separates sinus of vena cava from rest of right atrium) Found at union of smooth-walled "sinus venosus" portion and trabecular portion of right atrium Supplied by sinus node artery (usually a branch from right coronary)

Atrioventricular (AV) Node

Specialized conducting myocytes within tricuspid annulus near atrioventricular (membranous) septum

Subendocardial structure found within Koch triangle, an anatomic area defined by these 3 vertices Membranous septum Roof of coronary sinus ostium Tricuspid annulus at a point directly below coronary sinus ostium Supplied by AV nodal artery (usually from posterior descending artery)

This view of the opened right heart shows the location of Koch triangle: Atrioventricular septum , coronary sinus ostium , and tricuspid annulus below the coronary sinus ostium .

AV Node

Compact "bulb" of smaller polyhedral myocytes merging with larger stellate to spindled myocytes with vacuolar sarcoplasm toward His bundle Mesothelial-like cells and cystic structures occasionally intermixed AV nodal artery courses through AV node Connective tissue surrounds node, "insulating" adjacent myocardium Autonomic nerves and lymphatics seen in vicinity Rich supply of lymphatics may explain predilection for involvement in patients with sarcoidosis Lymphatic drainage of endogenous toxins from distal infarcted myocardium causes "stunning" of AV node and transient heart block post myocardial infarction in some patients

His Bundle and Bundle Branches

Constituent cells mostly smaller than myocardial myocytes and more vacuolated

Right bundle branch is smaller and cord-like Left bundle branch is larger and splays out over leftward ventricular septum

Purkinje Cell

Term applied to cells in left bundle branch and

MICROSCOPIC FINDINGS SA Node

Compact and polyhedral myocytes surrounded by

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dense collagenous tissue Sarcoplasm and cross-striations less prominent Sinus nodal artery courses through sinus node Autonomic nerve fibers and ganglia seen in vicinity Increased ratio of dense collagen to myocytes with increasing age reported

distal right bundle branch because they are larger than myocardial myocytes and have more vacuolar cytoplasm As with all conduction system cells, Purkinje cells are myocytes and contain myofibrils by electron microscopy Differ from normal cardiomyocytes by absence of T tubules and striking abundance of cell-cell junctions

Histochemical Stains

Conduction system myocytes differ from contractile myocytes Anaerobic oxidation predominates over aerobic

Unique cholinesterases expressed in conduction system myocytes Abundant glycogen found in conduction system myocytes

Strategies for Processing and Examining Conduction System Given small size of these structures

It is difficult to grossly cut tissue blocks thinly enough to evaluate different segments in a single histologic section Serial sectioning of paraffin blocks is necessary to identify structures and evaluate abnormalities Some authors advocate exhaustive sectioning of paraffin blocks (1,200-1,600 total slides) to evaluate every conduction system cell

Transient Antemortem Conduction Disturbances

Usually not associated with identifiable structural abnormality

MAJOR DISEASES AFFECTING CARDIAC CONDUCTION SYSTEM Congenital Atrioventricular Block Usually "benign" clinically

Eventual pacemaker therapy

Lack of connection to atrial myocytes Fatty replacement of AV nodal structures Fibrosis and septation (bands of fibrosis dividing nodal myocyte groups)

HISTOLOGIC PITFALLS AV Node and Bundle Branches

Normally occurring smooth muscle bundles in endocardium should not be mistaken for Purkinje cells or conduction system tracts

INDICATIONS FOR EXAMINATION OF CONDUCTION SYSTEM SA Node

Documented sinus node electrocardiographic abnormalities Tachycardia-bradycardia syndrome Sick sinus syndrome Sinus arrest Not atrial fibrillation or atrial flutter (in most cases, SA node is normal) Previous ablation procedure Sudden unexpected death without other cardiac cause(s) (pathologist’s discretion)

AV Node

Atrioventricular block

1st degree 2nd degree (Mobitz type 1 or Wenckebach type) 2nd degree (Mobitz type 2) 3rd degree Junctional arrhythmias Previous ablation procedure

His Bundle and Bundle Branches

Variable, generally not indicated Very difficult to localize pathways of interest Previous ablation procedure

Preexcitation Electrocardiographic Changes Classic example is Wolff-Parkinson-White syndrome Anomalous connecting band of contractile myocardium between atria and ventricle

Bypassing normal conduction delay coordinated in AV node

Careful examination of entire coronary groove can be undertaken to identify a "myocardial bridge"

Increased fibrosis of basal ventricular septal "summit"

Sarcoidosis

Predilection for subendocardium and conduction pathways

May relate to density of lymphatics in these areas Identical to sarcoidosis elsewhere Nonnecrotizing granulomas Fibrosis and chronic inflammation Infectious causes should be excluded

Organ System Approach to Autopsy: Sudden and Unexpected Death

CARDIAC CONDUCTION SYSTEM

Myocarditis

Conduction disturbance may occur in acute or chronic phase

Sinus node dysfunction usually reflect direct involvement of sinoatrial node myocytes

AV node dysfunction

Direct involvement by inflammation Stunning through lymphatic drainage of toxic substrates Can occur in all myocarditis etiologies Infections (viral, bacterial, fungal) Toxins (drug, chemotherapy) Hypersensitivity Autoimmune Ventricular arrhythmias also common in myocarditis Foci of electrical excitability in damaged ventricular myocardium

Cystic Tumor of AV Node Biologically indolent

Slow growing Never metastasizes May replace AV node entirely Wide age range at presentation Diverse electrocardiogram manifestations AV block (narrow QRS on EKG) Ventricular arrhythmias (wide QRS on EKG) Sudden death may be presenting sign Histopathology Variably sized epithelial-lined cysts Cyst lining ranging from squamoid (stratified) to simple cuboidal Fibroblastic stroma and hemorrhage surrounding cysts Often grossly inapparent

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Organ System Approach to Autopsy: Sudden and Unexpected Death

CARDIAC CONDUCTION SYSTEM Occasional mesenchymal heterotopia (chondroid, osseous)

Lengre Disease

Idiopathic fibrosis of AV node Heritable component Several genes implicated

Cardiac morphogenesis Cardiac structural proteins Cardiac ion channels Histopathology Fibrotic replacement, septation Fatty infiltrate Sparse inflammation in some cases

Others

Amyloid Ischemic heart disease

SA nodal artery is typically a primary branch of the proximal right coronary artery RCA territory infarction may be associated with direct AV node ischemic injury Left bundle branches are most vulnerable in septal wall infarction Chronic ischemia to nodal areas may result in increased fibrosis Metastasis Any primary site possible Disseminated lymphoma also reported

PATHOLOGY OF ENDOVASCULAR ABLATION PROCEDURES FOR ARRHYTHMIAS

SELECTED REFERENCES 1.

10.

Technical Aspects

Increasingly common due to improved imaging

guidance and catheter-based mapping and energy delivery Radiofrequency and high-frequency ultrasound energy Controlled "dose" delivery Catheter tip irrigation to limit scatter and improve precision

MR Mapping

11. 12. 13.

14.

Used at some centers

3D Endovascular Electrophysiologic Mapping Used to identify target areas

Complications

Possible injury to phrenic nerve, esophageal wall (in pulmonary vein isolation procedures)

Histopathologic Changes Acute

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Cautery-like thermal injury Infarct-like myocyte damage, edema, hemorrhage, with distinct borders Influx of neutrophils Chronic Discrete "punched out" areas of dense collagenous replacement fibrosis Sharp interface with surrounding normal myocardium

15. 16.

Jongbloed MR et al: Normal and abnormal development of the cardiac conduction system; implications for conduction and rhythm disorders in the child and adult. Differentiation. 84(1):131-48, 2012 Arbustini E et al: Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/ C defect-related disease. J Am Coll Cardiol. 39(6):981-90, 2002 Wang JN et al: Complete atrioventricular block following myocarditis in children. Pediatr Cardiol. 23(5):518-21, 2002 Gollob MH et al: Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med. 344(24):1823-31, 2001 Tan HL et al: A sodium-channel mutation causes isolated cardiac conduction disease. Nature. 409(6823):1043-7, 2001 McGuire MA et al: Atrioventricular junctional tissue. Discrepancy between histological and electrophysiological characteristics. Circulation. 94(3):571-7, 1996 Bharati S et al: Cardiac conduction system involvement in sudden death of obese young people. Am Heart J. 129(2):273-81, 1995 Michalsson M et al: Isolated congenital complete atrioventricular block in adult life. A prospective study. Circulation. 92(3):442-9, 1995 Bharati S et al: The conduction system findings in sudden cardiac death. J Cardiovasc Electrophysiol. 5(4):356-66, 1994 Gamache MC et al: Histopathological study following catheter guided radiofrequency current ablation of the slow pathway in a patient with atrioventricular nodal reentrant tachycardia. Pacing Clin Electrophysiol. 17(2):247-51, 1994 James TN: Congenital disorders of cardiac rhythm and conduction. J Cardiovasc Electrophysiol. 4(6):702-18, 1993 Bharati S et al: The conduction system in transplanted hearts. Chest. 102(4):1182-8, 1992 Kurosawa H et al: The conduction bundle at the atrioventricular junction. An anatomical study. Eur J Cardiothorac Surg. 3(4):283-7, 1989 Carter JB et al: Congenital heart block. Anatomic correlations and review of the literature. Arch Pathol. 97(1):51-7, 1974 Lev M et al: The pathogenesis of atrioventricular block in coronary disease. Circulation. 42(3):409-25, 1970 Lev M: The pathology of complete atrioventricular block. Prog Cardiovasc Dis. 6:317-26, 1964

Gross and Microscopic Features (Left) This superior view of the heart shows the location of the tissue block removed for examination of the sinoatrial node . The pulmonary artery , aorta , superior vena cava , and left atrium are labeled for orientation. (Right) Viewed from the endocardial aspect, this sinoatrial node tissue block consists of a portion of terminal crest with a few pectinate muscles attached. The overlying epicardium (not seen, facing down) is intact.

(Left) After serial sectioning the tissue block, the belly of the terminal crest is now seen in cross section in each piece. The pinpoint sinus nodal artery can also be seen in many of the sections, identifying the location of the sinoatrial node. (Right) This cross section illustrates the dense connective tissuerich sinoatrial node tissue surrounding the sinus node artery .

(Left) This sinoatrial node from a 52-year-old man with sinus node dysfunction shows prominent fatty infiltration of the sinoatrial node. The sinus node artery is otherwise normal . (Right) This sinoatrial node from a patient with sick sinus syndrome shows increased interstitial fibrosis (blue green) within the sinoatrial node. The sinus node artery is otherwise normal . Clinicalpathologic correlation is essential in such cases.

Organ System Approach to Autopsy: Sudden and Unexpected Death

CARDIAC CONDUCTION SYSTEM

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Organ System Approach to Autopsy: Sudden and Unexpected Death

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CARDIAC CONDUCTION SYSTEM

Gross and Microscopic Features (Left) This view of the opened right heart shows the defect after removing the tissue block containing the AV node (inside Koch triangle). The and superior vena cava pulmonary outflow tract are labeled for orientation. (Right) This view of the opened left heart demonstrates that the excised tissue block also includes a portion of anterior mitral valve leaflet (and aorto-mitral fibrous continuity).

(Left) The left-facing aspect of the AV node tissue block is shown here, with membranous septum and pockets of 2 aortic valve cusps labeled for orientation. (Right) Serial cross sections through the excised AV node tissue block illustrate portions of tricuspid valve leaflet , membranous (atrioventricular) septum , and aortic valve cusp . Occasionally, the AV nodal artery may be seen grossly in the tricuspid annular fibrosa (not seen here).

(Left) The proximal bulbar portion of the atrioventricular is shown here, node seated within the annular fibrosa and insulated from the myocardium proper by dense collagen (blue). A portion of tricuspid valve leaflet is shown for orientation. (Right) This image shows the more distal bundle branches straddling the septal myocardium. The branches emanate from the His bundle . The right bundle is thin and cord-like. The left bundle is typically thicker and splays widely across the septum.

Gross and Microscopic Features (Left) This AV node tissue block section from a sudden cardiac death autopsy shows a grossly variegated, illdefined mass lesion in the vicinity of the AV node. The aortic valve and tricuspid valve leaflets are labeled for orientation. (Right) Histologically, this mass shows multiple cystic structures lined by squamoid to cuboidal epithelium, features diagnostic of cystic tumor of the atrioventricular node.

(Left) This AV node section from cardiac allograft in a patient with Mobitz type 2 heart block shows cardiac allograft vasculopathy affecting the AV nodal artery and mononuclear inflammation associated with the AV node myocytes . (Right) This higher magnification view from the heart shows a mix of mononuclear cells with apparent injury to the AV nodal myocytes .

Organ System Approach to Autopsy: Sudden and Unexpected Death

CARDIAC CONDUCTION SYSTEM

(Left) This AV node section shows involvement by nonnecrotizing granulomatous inflammation , consistent with sarcoidosis. The AV nodal artery is shown for orientation. (Right) This image shows acute lymphocytic myocarditis involving the superior portion of the bulbar atrioventricular node. In addition to systolic heart failure, the patient developed AV block.

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Organ System Approach to Autopsy: Sudden and Unexpected Death

AORTIC DISSECTION

The Marfan syndrome phenotype includes a long thin body habitus with long limbs compared to trunk, long fingers (arachnodactyly), pectus excavatum, and scoliosis.

TERMINOLOGY Synonyms

Dissecting aneurysm, dissecting hematoma

Definitions

Presence of blood within media of aorta

ETIOLOGY/PATHOGENESIS Hypertension

Medial degenerative change (pressure and ischemia related)

Inherited or Acquired Connective Tissue Disorders

Fibrillin 1 (FBN1) gene mutation: Marfan syndrome type 1

TGFB receptor gene mutations: Marfan syndrome type 2 (classic Marfan phenotype with TGFBR2 mutation), Loeys-Dietz (TGFBR1 and TGFBR2) Various gene mutations (FBN1, TGFBR1, and TGFBR2) familial thoracic aortic aneurysm/dissection

CLINICAL ISSUES Epidemiology Incidence

~ 2,000 cases per year in USA

Age

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Usually older (> 60 years) If younger, suspicion for syndromic or nonsyndromic connective tissue disorder Gender M > F (2-3:1) Risk factors Hypertension, especially in older men

In Loeys-Dietz syndrome type 1, the phenotype includes hypertelorism (wide-set eyes) cleft palate/bifid uvula, and craniosynostosis. There is also overlap with Marfan phenotype.

Hereditary syndromes and nonsyndromic hereditary disorders of connective tissue Marfan syndrome, Loeys-Dietz syndrome (types 1 and 2), vascular Ehlers-Danlos syndrome, familial thoracic aortic aneurysm syndrome, autosomal dominant polycystic kidney disease Bicuspid aortic valve (2% of population, M > F); 5% develop dissection Congenital diseases/syndromes Turner syndrome, aortic coarctation, tetralogy of Fallot Acquired disorders of connective tissue Vitamin C deficiency, copper metabolism defects Iatrogenic Complication of cardiac surgery or cardiac catheterization and intraaortic balloon pump insertion Trauma Blunt trauma to thorax (vehicular accident) rarely causes dissection, most often full or partial rupture Pregnancy (late) or puerperium (rare)

Presentation

Clinical chart review

Presence of risk factors, family history

Symptoms may be variable

Acute aortic syndrome (pain related to disruption of aortic media) Obstruction of major branch vessels (MI, stroke, mesenteric angina) Aortic valve insufficiency (acute aortic insufficiency, congestive heart failure,shock) Rupture (cardiac tamponade, hypovolemic shock, hemothorax/peritoneum, retroperitoneal hematoma)

Laboratory Tests

Hemoglobin and hematocrit

Expect decrease but may be normal in very acute blood loss without volume replacement

Key Facts Clinical Issues

If younger, suspicion for syndromic or nonsyndromic connective tissue disorder

Imaging Findings

Widening of aortic silhouette or abnormal aortic contour on chest radiograph

May be normal in 12-15% of patients with aortic dissection

Macroscopic Pathology

Marfan syndrome: Thin habitus, long limbs (arm span > height), long digits (arachnodactyly)

Loeys-Dietz syndrome: Type 2 overlaps with vascular Ehlers-Danlos syndrome and Marfan syndrome Fewer craniofacial abnormalities (only bifid uvula), pectus, joint laxity and arachnodactyly but no marfanoid body habitus, easy bruising (may see bruises), soft velvety translucent skin Vascular Ehlers-Danlos syndrome: Fewer overall physical findings; small joints with mild hypermobility, soft velvety translucent skin and easy bruising (may see bruises on body) Turner syndrome: Short stature, shield-like chest, webbed neck, short 4th metacarpal

Loeys Dietz: Marfan features plus craniofacial abnormalities: Craniosynostosis, hypertelorism, bifid uvula &/or cleft palate

IMAGE FINDINGS Radiographic Findings

Widening of aortic silhouette or abnormal aortic contour on chest radiograph May be normal in 12-15% of patients with aortic dissection

CT Findings

CT more sensitive for detection of dissection

MACROSCOPIC FEATURES External Examination

Pallor, body habitus suggesting underlying syndromic connective tissue disorder Marfan syndrome: Thin habitus, long limbs (arm span > height), and long digits (arachnodactyly) are classic Pectus excavatum (caved in or concave appearance of anterior chest wall), scoliosis, highly arched palate with crowding of teeth, and occasional skin striae and joint laxity may also be seen Loeys-Dietz syndrome: Type 1 overlaps with Marfan syndrome with exceptions Craniofacial abnormalities: Craniosynostosis, hypertelorism, bifid uvula &/or cleft palate Loeys-Dietz syndrome: Type 2 overlaps with vascular Ehlers-Danlos syndrome and Marfan syndrome Fewer craniofacial abnormalities (only bifid uvula), pectus, joint laxity and arachnodactyly but no Marfanoid body habitus, easy bruising (may see bruises), soft velvety translucent skin Vascular Ehlers-Danlos syndrome: Fewer overall physical findings; small joints with mild hypermobility, soft velvety translucent skin and easy bruising (may see bruises on body) Turner syndrome: Short stature, shield-like chest, webbed neck, short 4th metacarpal Medical/surgical intervention

Incision from operative or other invasive intervention that lead to or was in response to dissection Sternotomy incisions, catheterization sites, abdominal incisions, etc.

Internal Examination

Organ System Approach to Autopsy: Sudden and Unexpected Death

AORTIC DISSECTION

Hemopericardium (blue appearance to unopened pericardium), hemothorax (usually left-sided), hemoperitoneum, retroperitoneal hematoma Measure amount of blood in any individual cavity Classic signs of hypovolemic shock occur with loss of 30-40% of blood volume (~ 1,500-2,000 cc) Normal adult blood volume ~ 77mL/kg, with BMI and age it decreases

Organ Examination Aorta and aortic valve

Remove aorta and heart together, attached, and keep at least 0.5 cm of major branch vessels Since most intimal tears are proximal, begin opening aorta distally and along posterior surface Examine intima as aorta is opened to identify area of intimal tear Most intimal tears within first 10 cm of aortic valve Look for distal aortic intimal tear (double-barrel aorta) Describe extent of dissection (proximal aorta, proximal and distal, distal aorta) Type A: Ascending or ascending and descending aorta Type B: Distal aorta without proximal involvement Examine closed aortic valve from outflow (aortic) surface for absence of coaptation of leaflets (aortic insufficiency) Assess for presence of bicuspid aortic valve: Fused cusp (usually right and left cusps fused, also called anterior fusion) Measure ascending aorta and aortic valve circumference

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Organ System Approach to Autopsy: Sudden and Unexpected Death

AORTIC DISSECTION Check major branch vessels along route of dissection (coronary, carotid, subclavian, etc.) for involvement by dissection and presence of luminal obstruction Identify site of rupture if present Section through intimal tear, intramural hematoma, involved branch vessels, and noninvolved aorta Operative repair changes Ascending aortic grafts aortic valve replacement/repair, coronary reimplantation or bypass Heart Examine coronary arteries and interatrial septum closely for evidence of proximal extension of dissection Right coronary artery involved more frequently than left coronary artery Check for gross evidence of myocardial ischemia, myocardial hypertrophy (heart weight, LV wall thickness) Subendocardial sampling (and papillary muscles): Area at highest risk for ischemia Congenital heart disease (unusual in adult) Tetralogy of Fallot (right ventricular hypertrophy, infundibular stenosis, ventricular septal defect, overriding aorta) Aortic coarctation (narrowing of aortic lumen usually in region of ductus arteriosus [ligamentum arteriosum]) may be seen independently or in Turner syndrome Kidneys Cortical pallor, infarct if dissection extends to renal artery Granular pitting of cortical surface, size due to hypertension Gastrointestinal tract Grossly examine for areas of ischemia especially "watershed areas" in transverse colon and splenic flexure Infarct due to direct involvement of mesenteric artery by dissection CNS Infarction related to obstruction of major vessels, lacunar infarcts from longstanding hypertension Lacunar infarcts are small cystic areas in basal ganglia, subcortical white matter, and pons

MICROSCOPIC PATHOLOGY Histologic Features Aorta

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Intramural hematoma in media between inner 2/3 and outer 1/3; may show organization and neointima over time Noninvolved aorta with varying degrees of medial degeneration, with cystic medial degeneration being most severe Cystic medial degeneration: Fragmentation of elastic lamellae with formation of cystic spaces that are rich in mucopolysaccharides

Aortic valve

May show myxoid changes

Heart

Enlarged myocyte nuclei (hypertrophy) and perivascular fibrosis (hypertension changes) Diffuse subendocardial coagulative myocyte necrosis (ischemia due to global hypoperfusion) Due to hemorrhagic complication of dissection Coagulative myocyte necrosis in territory of involved vessel Due to involvement of coronary artery by dissection Kidneys Hyaline arteriolosclerosis, small cortical scars, arterial sclerosis (hypertensive changes) Coagulative necrosis (infarct) Gastrointestinal tract Coagulative necrosis of epithelium, fibrin thrombi in submucosal vessels (ischemic injury) CNS Hypertensive arteriolosclerosis, lacunar infarcts (small: < 15 mm) subcortical (basal ganglia, thalamus, pons, internal capsule) infarcts due to arterial sclerosis of single branch of a deep penetrating artery, cerebral hemorrhage Due to dissection: Cerebral infarction in territory of an involved artery

ANCILLARY TESTS Histochemistry

Elastic Van Gieson: Highlights disruption of elastic lamellae and areas of cystic medial degeneration

Alcian Blue pH 2.5 highlights acid

mucopolysaccharides in areas of cystic medial degeneration

REPORTING CRITERIA Final Report

Document type of dissection (type A or B proximal aortic involvement), site of intimal tear, site of rupture and amount of hemorrhage, involvement of major branches and associated complications, any surgical interventions Underlying risk factors for aortic dissection If considered to be possible hereditary syndrome, recommend follow-up evaluation for immediate family

SELECTED REFERENCES 1. 2.

Pyeritz RE: Heritable thoracic aortic disorders. Curr Opin Cardiol. 29(1):97-102, 2014 Van Laer L et al: Loeys-Dietz syndrome. Adv Exp Med Biol. 802:95-105, 2014

Gross Features (Left) This hemopericardium with liquid and clotted blood surrounding the heart was noted in a case of aortic dissection with proximal rupture and clinical cardiac tamponade. (Right) There is liquid blood and blood clot in this left pleural cavity associated with compression of the left lung , due to rupture of an aortic dissection. (From DP: Cardiovascular.)

(Left) In this aorta, there were 2 intimal tears distal to the subclavian ostium . One tear extended proximally into an aortic dissection. The other tear did not progress. (Right) In this aortic dissection there was a very large (almost circumferential) intimal tear in the proximal aorta . The outer tissue present between the edges of the tear represents the outer aspect of the dissection .

Organ System Approach to Autopsy: Sudden and Unexpected Death

AORTIC DISSECTION

(Left) This ascending aorta with dissection is markedly dilatated , a risk factor for dissection. (Right) This cross section through an aortic dissection shows medial blood clot located between the thicker inner and thinner outer portions of the media. (From DP: Cardiovascular.)

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Organ System Approach to Autopsy: Sudden and Unexpected Death

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AORTIC DISSECTION

Aortic Dissection Extension and Risk Factors (Left) The probe in this aorta extends distally from an intimal tear within the false lumen of a dissection that involved the entire distal aorta to the iliac arteries. (Right) There was involvement of the left renal artery in this aortic dissection with an intimal flap from the left renal artery protruding into the lumen of the aorta.

(Left) This dissection highlights a bicuspid aortic valve that is viewed from the outflow (aortic) surface (abnormal cusp ) and cross sections through the associated aortic dissection (false lumen ). Of patients with bicuspid aortic valve, 5% will develop aortic dissection. (Right) A probe highlights the luminal narrowing in a resected segment of aorta with aortic coarctation. The intima is thickened and wrinkled , and the wall is thick .

(Left) This heart demonstrates concentric hypertrophy with left ventricular wall thickening , as is often seen in hypertensive patients with aortic dissection. In addition, subendocardial infarction is present , as may be seen in hypovolemic shock after rupture of an aortic dissection. (Right) Hypertensive renal changes such as nephrosclerosis are common in patients with aortic dissection. This kidney demonstrates the granular cortical surface seen in nephrosclerosis.

Operative Intervention and Microscopic Features (Left) This heart and thoracic aorta specimen shows surgical replacement of the ascending aorta with a Dacron graft . There is also dissection of the descending thoracic aorta with a false lumen evident . (From DP: Cardiovascular.) (Right) This is an example of an ascending aorta repair with a Dacron graft ; the intimal tear can be seen proximal to the graft , and pledgeted sutures have been used to repair the aortic valve. (From DP: Cardiovascular.)

(Left) Microscopic section through an aortic dissection shows the intramural hematoma located between the inner 2/3 and outer 1/3 of the aortic wall. The intima is on the bottom right and the adventitia is on the upper left. (From DP: Cardiovascular.) (Right) Elastic stain highlights the fragmentation of the elastic lamellae along the intramural hematoma .

(Left) Cross section through an aorta with a chronic dissection shows neointimal hyperplasia and unorganized hematoma along the false lumen . The false lumen plane is in the outer aspect of the media between the inner 2/3 and outer 1/3 . (Right) Elastic-stained aortic media demonstrates areas of elastic lamina fragmentation with cystic areas of accumulated mucopolysaccharides (cystic medial degeneration). (From DP: Cardiovascular.)

Organ System Approach to Autopsy: Sudden and Unexpected Death

AORTIC DISSECTION

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ABDOMINAL AORTIC ANEURYSM

This infrarenal, saccular abdominal aortic aneurysm (AAA) is distal to the superior mesenteric artery and renal arteries (not well visualized) and ends at the iliac vessels .

TERMINOLOGY

Definitions

MACROSCOPIC FEATURES

Abdominal aortic aneurysm (AAA)

CLINICAL ISSUES Epidemiology Gender

M > F (4:1)

Major risk factors

Nonmodifiable: age, male gender, family history Modifiable: Hypertension, hyperlipidemia, smoking, diabetes

Presentation

Usually due to complications of aneurysm/endografts

Rupture (abdominal pain/shock), emboli, compression (e.g., ureterazotemia), fistula (massive GI hemorrhage), infection (sepsis/shock), endoleaks

Laboratory Tests

Hyperhomocysteinemia, hyperlipidemia, C-reactive protein (risk factor assessment)

hemoglobin/hematocrit (normal if acute rupture, with slow leak), creatinine (acute tubular injury)

Blood culture (infected aneurysm)

(EVAR) endoleak

Other atherosclerotic complications (MI, stroke)

of vessel wall with diameter at least 50% > normal Normal diameter with age, varies with aortic location and body habitus Abdominal aortic diameter < 3 cm

History of intervention: Endovascular aneurysm repair

Abbreviations

Aneurysm: Localized permanent pathologic dilatation

Obstructive complications of AAA include major branch obstruction. This juxtarenal AAA is associated with obstruction of the left renal artery as denoted by the atrophic left kidney .

Clinical Chart Review

Risk factors for atherosclerosis/aneurysm, family history, clinical presentation suggestive of rupture/ other complication

External Examination

Pallor &/or distended abdomen (rupture) Lower extremity changes related to aortic atherosclerotic disease/aneurysm Loss of hair, thin skin, muscle atrophy, erythema, blue toe (embolic) Abdominal incision (aneurysm repair) Signs of risk factors for atherosclerosis Xanthelasma (hypercholesterolemia) Diagonal earlobe crease (Frank sign) (more sensitive in younger patients)

Internal Examination

Hemoperitoneum or retroperitoneal hematoma

Organ Examination Aneurysm

Describe shape, length, position in relation to renal artery ostia (supra-/juxta-/infrarenal) and diameter Rupture risk with diameter; 4-5 cm 1% per year, 5-6 cm 11% per year, 6 cm 25% per year: Repair usually at 5.5 cm Abdominal or aorta x-ray highlights endografts Review recent imaging; history of endoleaks Look for rupture if hemoperitoneum or retroperitoneal hematoma present Most common site: Left lateral infrarenal Endoleaks: Continued growth of aneurysm due to continued perfusion after endograft Type I at graft anastomosis, type II from branch vessels, type III between stents/ruptured graft, type IV through porous graft, type V unknown

Key Facts Macroscopic Pathology

Clinical diagnosis but recent thrombus around stent supports diagnosis, and radiograph of stent can identify rupture of graft Aneurysm interior examination Open aneurysm posteriorly examine contents, relationship to/obstruction of branch vessels, presence of rupture Describe stent appearance, location, adherence to underlying aortic wall, obstruction of ostia Graft can be kept intact with sampling of aneurysm around graft Systemic atherosclerosis complications Acute/chronic MI, cerebral infarcts

MICROSCOPIC PATHOLOGY

Most common site: Left lateral infrarenal

Microscopic Pathology

Complications: Atheroemboli thrombosis/ vasculitis, infarcts (kidney, intestine, brain, spleen)

Top Differential Diagnoses

IgG4-related disease/inflammatory aortic aneurysm Marked storiform adventitial fibrosis with extensive plasma cell infiltrate, composed of high percentage of IgG4 cells

ANCILLARY TESTS Histochemistry

Gram stain in cases of suspected infected aneurysms

Immunohistochemistry

IgG4/IgG to exclude IgG4 disease (estimate % IgG4positive cells)

DIFFERENTIAL DIAGNOSIS IgG4-Related Disease/Inflammatory Aortic Aneurysm Marked storiform adventitial fibrosis with extensive

plasma cell infiltrate, composed of high percentage of IgG4 cells

Histologic Features

Aneurysm: Atherosclerosis with marked degeneration of media, marked acute inflammation indicates possible infection (rare), malignancy related to stent (rare) Rest of cardiovascular system Coronary/carotid atherosclerosis acute plaque events (rupture, thrombosis) Acute/chronic myocardial infarction, acute subendocardial ischemia (terminal shock) Other: Emboli/shock Atheroemboli thrombosis/vasculitis, infarcts (renal, intestine, spleen), acute tubular injury

Organ System Approach to Autopsy: Sudden and Unexpected Death

ABDOMINAL AORTIC ANEURYSM

REPORTING CRITERIA Aneurysm Incidental or Cause of Death

Identify complications and risk factors for aneurysm

SELECTED REFERENCES 1.

Kent KC: Clinical practice. Abdominal aortic aneurysms. N Engl J Med. 371(22):2101-8, 2014

IMAGE GALLERY

II (Left) This cloth-covered stent is attached proximally to the aorta beneath the renal artery ostia .(Courtesy J. Chiaffarano, MD.) (Center) This ruptured infrarenal aneurysm has an endovascular stent . The aneurysm wall is thin, and there is hematoma around the distal and may elicit a reactive aneurysm due to rupture. (Courtesy S.A. Rahimi, MD.) (Right) Atheroemboli usually contain cholesterol crystals vasculitis .

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Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY EDEMA

Pleural surface shows prominent interlobular septal markings as a consequence of excess fluid within the interstitial lymphatics that is present with severe pulmonary edema.

TERMINOLOGY Definitions

Accumulation of fluid in alveolar spaces

2 main etiologic categories Cardiogenic pulmonary edema (CPE) (also referred to as hemodynamic edema) Noncardiogenic pulmonary edema Pathogenetic classification based on integrity of alveolar-capillary unit and intrinsic permeability of microvasculature Nonpermeability edema of intact alveolarcapillary unit, usually seen with hydrostatic pressure; may also be due to oncotic pressure, lymphatic obstruction, and other less well understood factors Permeability edema: Disruption of alveolarcapillary unit due to endothelial &/or epithelial damage Diffuse alveolar damage (DAD) is classic noncardiogenic permeability edema and usual pathology seen in clinical acute respiratory distress syndrome (ARDS) "Diffuse" refers to damage to all parts of alveolus, but not to widespread lung injury DAD may be localized, but when clinically significant is usually widespread throughout lung

ETIOLOGY/PATHOGENESIS Pathogenesis

Lung fluid exchange based on Starling Law (balance

II 1 32

of intra- and extravascular hydrostatic and oncotic pressures), normal permeability of microvasculature, and reserve capacity of lymphatics Normal alveolar wall (alveolar/capillary unit) highly specialized to facilitate gas exchange

Gross appearance of pulmonary edema reflects the accumulation of fluid within the alveolar spaces.

Normally, capillary endothelium is semipermeable to protein; allows escape of fluid and low molecular weight substances Type I alveolar epithelial cells and endothelial cells are very thin and susceptible to damage Direct injury to endothelium allows for escape of fibrin-rich exudates into interstitium and airspaces Epithelial damage epithelial necrosis, surfactant due to type II alveolar pneumocyte injury and alveolar collapse CPE: Cardiac disease accumulation of blood in pulmonary vasculature (passive congestion) increased hydrostatic pressure transudation of fluid from microvasculature into alveolar spaces Acute passive congestion small endothelial breaks some release of red blood cells (alveolar microhemorrhage) in addition to fluid Chronic passive congestion repetitive alveolar microhemorrhage, hemosiderin-laden macrophages ("heart failure cells") Noncardiogenic pulmonary edema: Mechanism of injury that transudation/exudation of fluid varies according to etiology In all cases, fluid in alveoli impairs gas exchange and can be fatal

Etiology

Cardiogenic pulmonary edema

Ischemic and valvular heart disease, cardiomyopathy, myocarditis, cardiotoxic drugs and systemic toxins, hypertension and diabetes Noncardiogenic pulmonary edema including etiologies associated with diffuse alveolar damage Infections Pulmonary viral infections and sepsis (often with associated disseminated intravascular coagulation) Trauma

Key Facts Terminology

Pulmonary edema is accumulation of fluid in alveolar spaces

Etiology

Pulmonary edema divided into cardiogenic and noncardiogenic causes Diffuse alveolar damage is the prototypical example of noncardiogenic, permeability edema Major histologic pattern associated with clinical syndrome of acute respiratory distress syndrome In hospitalized patients, etiology of pulmonary edema or diffuse alveolar damage is often multifactorial

Major trauma and burns (burns often associated with smoke injury), fat embolism subsequent to trauma, near drowning Chemical, toxin, drug, radiation exposure Gastric acid (aspiration), smoke and other inhaled toxins (gases and chemicals), adverse drug reaction (including recreational drugs, oxygen toxicity, radiation injury, uremia) Hypoalbuminemic states Nephrotic syndrome, protein-losing enteropathies, chronic liver disease Iatrogenic Volume overload Unknown exact mechanism of injury Transfusion-related acute lung injury (TRALI), pancreatitis, high altitude pulmonary edema Disseminated intravascular coagulation (DIC) Cardiopulmonary bypass Multifactorial, and in some cases may be associated with adverse reaction to protamine used to reverse heparin anticoagulation Multifactorial/unknown Pulmonary thromboembolism Renal artery stenosis (often bilateral) Eclampsia Neurogenic Lymphatic obstruction Pulmonary vein obstruction

CLINICAL ISSUES Presentation

Depending on etiology, symptoms of pulmonary edema may appear suddenly or develop over time Symptoms include shortness of breath, dyspnea, wheezing, cough, anxiety, chest pain, and rapid weight gain from build-up of fluid in body

Clinical Issues

Significant cause of morbidity and mortality in hospitalized patients and is a common finding at autopsy

Macroscopic Pathology

Heavy and fluid-filled lungs Diffuse alveolar damage results in airless and firm lungs

Microscopic Pathology

Nonpermeability pulmonary edema

Fluid accumulation within alveolar spaces

Diffuse alveolar damage

Hyaline membranes (early) and fibroblastic proliferation (late)

MACROSCOPIC FEATURES General Features

Effect of formalin perfusion of lung on evaluation of pulmonary edema has long been debated Cutting lungs in a fresh state enhances appreciation of pulmonary edema and might be appropriate in some circumstances and is favored by some pathologists However, perfusion of lung allows for better overall appreciation of many other pathologic processes such as infection, parenchymal disease, and malignancy (many of which coexist in a hospital autopsy population), and perfusion is therefore recommended Even with perfusion, it is still possible to satisfactorily document pulmonary edema by observation, pre-perfusion lung weights, and microscopic sections

Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY EDEMA

External Examination

Pulmonary edema often occurs in setting of congestive heart failure Pitting edema and venous stasis changes may be present Severe edema (anasarca) noted in hypoalbuminemic states Rapid infusion of fluids may result in iatrogenic volume overload and subsequent acute pulmonary edema Note IV access and other central lines and correlate with clinical history of fluid administration as well as transfusions Sternal incision from recent coronary artery bypass graft surgery, valve surgery, ventricular assist device Burns (not encountered in hospital autopsy practice) Gastric contents in mouth (aspiration) Recent cesarean section scar (eclampsia-related pulmonary edema)

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Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY EDEMA Late phase (also referred to as proliferative or organizing phase) Fibroblastic proliferation and type II pneumocyte hyperplasia predominate Squamous metaplasia

Internal Examination

Absence or presence and character/quantitation of pleural effusions Pleural effusion occurs when reserve capacity of lymphatic system to drain fluid from pulmonary extravascular spaces is exceeded and it is a good indicator of excess fluid in lungs Cardiac disease is the major cause of nonpermeability pulmonary edema Special attention should be paid to examination of the 4 heart chambers, cardiac valves, coronary vessels, and major vessels for any abnormality Renal disease or renal artery stenosis can also cause noncardiogenic, nonpermeability pulmonary edema

Organ Examination

DIFFERENTIAL DIAGNOSIS Acute Fibrinous and Organizing Pneumonia (AFOP) Alveolar spaces filled with organizing balls of fibrin rather than classic hyaline membranes found in diffuse alveolar damage

Increased lung weights are a sensitive indicator of

DIAGNOSTIC CHECKLIST

pulmonary disease and, in absence of another etiology such as infection or malignancy, reflect severity of fluid accumulation within lung Prominent interstitial markings are often present on pleural surface and reflect accumulation of fluid within lobular interstitium Sectioning of unfixed lung will result in exudation of fluid from cut surface Assuming no other underlying pulmonary disease or longstanding cardiac disease resulting in chronic passive congestion, lungs in cardiogenic and noncardiogenic, nonpermeability pulmonary edema are fairly compliant By contrast, lungs with evolving diffuse alveolar damage are airless and firm Presence of frothy fluid exuding into trachea and bronchi prior to fixation is another indication of pulmonary edema

Pathologic Interpretation Pearls

In cardiogenic pulmonary edema, etiology is often directly attributable to a specific injury such as acute myocardial infarction In hospitalized patients, particularly within an intensive care setting, etiology of pulmonary edema or diffuse alveolar damage is often multifactorial Include major contributory causes when multifactorial

REPORTING CRITERIA Pulmonary Edema as Primary or Contributory Cause of Death

Example: Patient maintained on life support after major intracerebral hemorrhage eventually sustains cerebral herniation and expires, lungs with permeability pulmonary edema Permeability edema is a contributory cause of death

MICROSCOPIC PATHOLOGY Histologic Features

Nonpermeability pulmonary edema

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Fluid-filled alveolar spaces with pale granular eosinophilic precipitate, even with prior formalin perfusion Most prominent changes are often in lower lobe sections where hydrostatic pressure is most increased Alveolar capillaries are often distended reflecting antecedent capillary congestion Additional finding of increased hemosiderin-laden macrophages supports a diagnosis of chronic passive congestion in appropriate clinical setting Permeability pulmonary edema (diffuse alveolar damage) Early phase (also referred to as acute or exudative phase) Hyaline membranes (formed by escape of fibrinrich exudates and epithelial cell necrosis) Interstitial edema Alveolar collapse secondary to loss of surfactant Fibrin thrombi reflecting endothelial damage

SELECTED REFERENCES 1. 2.

Mac Sweeney R et al: Acute lung failure. Semin Respir Crit Care Med. 32(5):607-25, 2011 Matthay MA et al: The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol. 6:147-63, 2011 Beasley MB: The pathologist’s approach to acute lung injury. Arch Pathol Lab Med. 134(5):719-27, 2010

Pulmonary Edema and Early Diffuse Alveolar Damage (Left) Gross photograph demonstrates pulmonary edema with fluid exuding from the fresh cut surface of the lung. (Right) Early diffuse alveolar damage with a beefy red cut surface is seen in this gross photo. The lung is palpably firm and airless.

(Left) Low-power image of pulmonary edema shows fluid-filled alveolar spaces . (Right) Low-power view shows acute diffuse alveolar damage with hyaline membranes .

Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY EDEMA

(Left) High-power photo shows pulmonary edema. Even with prior formalin fixation, there is a patchy pale granular eosinophilic precipitate . (Right) Highpower view shows acute diffuse alveolar damage and hyaline membrane . The adjacent alveolar wall is edematous , and there are desquamated epithelial cells .

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Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY HEMORRHAGE

Diffuse pulmonary hemorrhage imparts a dark-red appearance to the lung parenchyma.

DAH in Goodpasture syndrome has a bland appearance without vasculitis or necrosis of alveolar septa (note intact septa ).

TERMINOLOGY Definitions

Diffuse alveolar hemorrhage (DAH) refers to accumulation of intraalveolar red blood cells that originate from pulmonary microcirculation Excludes other intraparenchymal and extrapulmonary sources of blood

ETIOLOGY/PATHOGENESIS Pathogenesis

All DAH is result of injury to pulmonary

II 1 36

microcirculation: Pathogenetic classification: Seropositive systemic vasculitides and autoimmune disorders, coagulation disorders, drug toxicity, and infections ANCA-associated vasculitides Granulomatosis with polyangiitis (Wegener granulomatosis) Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (uncommon) Goodpasture syndrome (antiglomerular basement membrane [GBM] disease) Isolated pulmonary capillaritis (seronegative vasculitis limited to lung) Autoimmune Systemic lupus erythematosus (SLE): ~ 4% of patients with SLE have DAH, usually associated glomerulonephritis Uncommonly associated with DAH: Rheumatoid arthritis, scleroderma, mixed connective tissue disorder, polymyositis, antiphospholipid antibody syndrome, cryoglobulinemia, Henoch-Schnlein purpura/IgA nephropathy, Behet syndrome Pre- and postmortem serologic studies, immunofluorescence and ultrastructural studies

should help identify and distinguish among autoimmune disease Drug (therapeutic and recreational) toxicity Cytotoxic drugs: Cyclophosphamide, mitomycin, cytarabine Anticoagulants Chelator: Penicillamine Antithyroid medication: Propylthiouracil (may be via drug-induced ANCA-mediated vasculitis) Crack cocaine inhalation Infection H1N1 and other viral and bacterial infections and parasitic infestation Bone marrow/stem cell transplantation Radiation therapy Idiopathic pulmonary hemosiderosis Rare disease usually seen in children characterized by recurrent episodes of DAH with resultant fibrosis and hemosiderosis Pathogenesis unknown Malignancy Kaposi sarcoma and metastatic malignancy

CLINICAL ISSUES Presentation

Most common presenting symptom is hemoptysis; however, hemoptysis absent in up to 1/3 of patients Hemoptysis may be abrupt in onset or slowly evolve over period of days to weeks Other symptoms and signs include fever, cough, chest pain, dyspnea, and anemia Radiographs demonstrate nonspecific diffuse pulmonary infiltrates Sequential bronchoalveolar lavage (BAL) can be confirmatory in patients without obvious hemoptysis

Key Facts Terminology

Diffuse alveolar hemorrhage is accumulation of intraalveolar red blood cells that originate from pulmonary microcirculation

Etiology

Result of injury to pulmonary microcirculation Pathogenesis varies according to etiology Differential diagnosis includes seropositive systemic vasculitides and autoimmune disorders, coagulation disorders, drug toxicity, and infections

Clinical Issues

Patients often (but not always) present with hemoptysis, diffuse radiographic pulmonary infiltrates, and hypoxemic respiratory failure

Prognosis

Most patients develop hypoxemic respiratory failure that is often severe and fatal

MACROSCOPIC FEATURES External Examination

Examine skin and extremities for signs of generalized thrombocytopenia or coagulation disorder Skin petechiae, mucosal petechiae, or oral blood Check for rash that may indicate drug reaction, vasculitis, or autoimmune disorder

Internal Examination

Check for internal signs of generalized thrombocytopenia, coagulation disorder, vasculitis, or autoimmune disorder Evidence of active or remote episodes of pleuritis, pericarditis, and abdominal serositis may indicate underlying connective tissue disease Look for shaggy serosal surfaces (acute), fibrosis/ adhesions (chronic)

Organ Examination Lungs

Obtain fresh tissue for immunofluorescence Alveolar hemorrhage should involve lung diffusely Consider alternative diagnosis for more localized patterns of blood Alveolar hemorrhage can be distinguished from pulmonary edema by consolidation and exudation of blood from cut surface, even after formalin perfusion and fixation Kidneys Renal involvement is a prominent feature of ANCAassociated granulomatosis with vasculitis (Wegener granulomatosis), SLE, and Goodpasture syndrome Petechiae (flea-bitten appearance), edema of kidneys Obtain fresh samples for immunofluorescence and electron microscopic studies

Macroscopic Pathology

Diffusely heavy and blood-filled lungs with exclusion of localized sources of bleeding

Microscopic Pathology

Intraalveolar red blood cells and fibrin with accumulation of hemosiderin-laden macrophages and organizing pneumonia in later phase 3 major histologic patterns Pulmonary capillaritis Bland hemorrhage Diffuse alveolar damage

Diagnostic Checklist

Clinical history and ancillary studies are essential for diagnostic interpretation

Skin

May be involved in autoimmune diseases Sample rashes, petechiae, purpura Collect fresh tissue for immunofluorescence

MICROSCOPIC PATHOLOGY

Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY HEMORRHAGE

Histologic Features

Lung: Intraalveolar red blood cells and fibrin with accumulation of hemosiderin-laden macrophages and organizing pneumonia over time 3 major histologic patterns are associated with diffuse alveolar hemorrhage Pulmonary capillaritis Interstitial neutrophilic infiltrate, leukocytoclasia, and fibrinoid necrosis of alveolar walls Bland alveolar hemorrhage (classic for Goodpasture syndrome but other potential etiologies) Diffuse alveolar damage Although less common cause of DAH, consider infectious etiology Secondary infection as a result of immunosuppressive therapy is common Common infections associated with DAH in immunocompromised patients Cytomegalovirus, adenovirus, invasive aspergillosis, Mycoplasma, Legionella, Strongyloides Common infections associated with DAH in immunocompetent patients Influenza (H1N1), dengue, leptospirosis, malaria, Staphylococcus aureus Appropriate microbiologic/virologic studies should be performed, such as nasal swab for suspected H1N1 Kidney: Glomerular inflammation/necrosis/crescent (glomerulitis), red blood cell casts in tubules associated with glomerulonephritis and also may indicate anticoagulant effect (warfarin nephropathy)

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Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY HEMORRHAGE Cytologic Features

Bronchoalveolar lavage with fresh and degenerated red blood cells, hemosiderin macrophages May also reveal evidence of viral/bacterial infection, parasitic infestation, or malignancy

ANCILLARY TESTS Immunofluorescence

Procure fresh frozen lung, kidney, or skin (if rash present) for full immunofluorescence panel with immunoglobulin and complement staining Diffuse, linear alveolar capillary and glomerular capillary basement membrane staining with IgG indicates Goodpasture syndrome Granular deposits of immune complexes (immunoglobulin and complement) SLE and other connective tissue disorders Glomerulonephritis associated with infection (e.g., Staphylococcus) Cryoglobulinemia HSP (IgA dominant immune complex deposit in glomeruli) Skin immunofluorescence may reveal immunoglobulin complement deposition in lesions of SLE, vascular IgA deposition in HSP, immunoglobulin and light chain deposition in cryoglobulinemia

Serologic Testing

Premortem serum should be sequestered and postmortem serum obtained by cardiac puncture Seropositivity may be rapidly diminished by initiation of immunosuppressive therapy or plasmapheresis ANCA, anti-GBM, ANA, and expanded panel of connective tissue disease serologies as indicated

Electron Microscopy Transmission

In DAH with renal involvement (pulmonary renal syndrome), may help in differential diagnosis Disruption of GBM with fibrin and inflammatory cells indicate crescent formation (ANCA, antiGBM, occasional lupus) Electron-dense immune complex-type deposits (not seen in ANCA or anti-GBM disease) support SLE or other connective tissue disorder Deposits with organized appearance (tubular or thumbprint [SLE, fibrillary], cryoglobulin)

Bronchial Arterial Bleeding

Common source of blood with bronchiectasis or chronic cavitary lesions

Extrinsic Blood

Aspirated blood from gastrointestinal source Aspirated blood from upper respiratory source

Malignancy

Metastatic angiosarcoma as well as Kaposi sarcoma may present with extensive alveolar hemorrhage

Outflow Obstruction

Postsurgical acute pulmonary venous outflow obstruction with lung transplantation

Cardiac causes such as mitral stenosis and mitral regurgitation in addition to pulmonary venoocclusive disease

Traumatic Injury or Postsurgical Bleeding

Also includes cardiopulmonary resuscitation (CPR)

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls

Gross and histologic findings of diffuse alveolar hemorrhage are not specific as to etiology

If possible, premortem serum samples should be sequestered and postmortem blood should be obtained for serologic studies Fresh frozen lung tissue should be procured for immunofluorescence, if indicated Clinical history and premortem laboratory data should be carefully reviewed for evidence of evolving coagulation disorder, thrombolytic therapy complications, infection, and drug toxicity Common etiologies for alveolar hemorrhage in hospital setting, particularly if patient did not initially present with findings suggesting diffuse alveolar hemorrhage syndrome

REPORTING CRITERIA Presence/Extent of DAH Was DAH cause of death Etiology of DAH if known

SELECTED REFERENCES 1. 2.

DIFFERENTIAL DIAGNOSIS Pulmonary Arterial Bleeding

Small, medium, or large-sized pulmonary vessels

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involved by vasculitides such as ANCA-positive granulomatous vasculitis, microscopic polyangiitis, and Churg-Strauss syndrome Other causes of thromboembolism with adjacent infarction

3. 4. 5.

West S et al: Diffuse alveolar haemorrhage in ANCAassociated vasculitis. Intern Med. 52(1):5-13, 2013 Marchiori E et al: Diffuse alveolar hemorrhage in infectious diseases. Chest. 139(1):228, 2011 McCabe C et al: Pulmonary-renal syndromes: an update for respiratory physicians. Respir Med. 105(10):1413-21, 2011 Lara AR et al: Diffuse alveolar hemorrhage. Chest. 137(5):1164-71, 2010 Colby TV et al: Pathologic approach to pulmonary hemorrhage. Ann Diagn Pathol. 5(5):309-19, 2001

Gross and Microscopic Appearance of Diffuse Alveolar Hemorrhage (Left) Immunofluorescence study of lung from the same patient with DAH reveals linear IgG deposition in the alveolar walls, supporting the diagnosis of Goodpasture syndrome. (Right) In antiGBM disease, there is strong linear staining with IgG along the glomerular capillary basement membrane . Anti-GBM antibody is most often IgG subclass 1 or 3 and rarely IgA or M. The antigen is the NC1 domain of the alpha 3 chain of type IV collagen.

(Left) The glomerular tuft in this glomerulus is difficult to see because of a circumferential crescent . Crescents can be seen in many renal diseases but are most often associated with anti-GBM disease or ANCA vasculitis. (Right) In this example of DAH due to neutrophilic capillaritis, there is interstitial neutrophilia as well as a background of acute intraalveolar hemorrhage (intact, nondegenerated red blood cells without hemosiderin macrophages).

Organ System Approach to Autopsy: Sudden and Unexpected Death

PULMONARY HEMORRHAGE

(Left) This lung section from a patient with terminal thrombocytopenia demonstrates nonspecific acute intraalveolar hemorrhage and fibrin . (Right) This is an example of nonspecific hemorrhagic foci in a coagulopathic patient. Microscopic sections should always be taken to exclude the possibility of infection.

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Organ System Approach to Autopsy: Sudden and Unexpected Death

TENSION PNEUMOTHORAX

This photograph shows the technique for demonstrating pneumothorax using a pocket of water and scalpel incision under the water and into the chest wall .

TERMINOLOGY Definitions

Air in pleural space

Classified as simple or tension pneumothorax Tension pneumothorax: Progressive accumulation of entrapped air in pleural space that pressureinduced displacement of mediastinum and heart; may result in potentially fatal hemodynamic compromise Primary (spontaneous) pneumothorax: Pneumothorax in patients with no known underlying lung disease Secondary pneumothorax: Pneumothorax associated with known underlying lung disease, trauma, or iatrogenic injury Pleural bleb: Airspace within pleura and separated from pleural space and alveoli by thin pleural membrane that may rupture and lead to pneumothorax Bullae: Airspaces that are characteristically subpleural and associated with destruction of lung tissue Pneumomediastinum, pneumopericardium, pneumoperitoneum, and subcutaneous emphysema: Air in mediastinum, pericardial space, peritoneal cavity, or subcutaneous tissue

ETIOLOGY/PATHOGENESIS Pathogenesis

Injury to lung or pleura communication between airspace and pleural space with so-called valve effect

When valve is created, air accumulates in pleural

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cavity during respiratory cycle Valve is 1-way only, allowing for entry of air during inspiration but not for its escape during expiration Accumulation of air intrapleural pressure and interferes with lung expansion on pneumothorax side

This opened chest cavity demonstrates collapse of the left lung with tension pneumothorax in a patient with widely metastatic carcinoma.

intrapleural pressure effect of ipsilateral lung collapse and pushes mediastinal structures and heart toward opposite side Compression of vena cava and right heart compromises venous return, diastolic filling, and cardiac output Significant shunting with ventilation-perfusion mismatch leads to hypoxemia, acidosis, and shock Decompression of pleural space must be prompt to avoid fatal hemodynamic compromise If air escapes into interstitial tissue planes, pneumomediastinum, pneumopericardium, pneumoperitoneum, and subcutaneous emphysema may result

Etiology of Pneumothorax Primary

Unknown; also termed spontaneous idiopathic pneumothorax Entity occurring in relatively younger patients that appears related to rupture of small peripheral and usually apical blebs Secondary pneumothorax Trauma including esophageal rupture and foreign body obstructing bronchus Iatrogenic Lung or pleural biopsy, thoracotomy, mechanical ventilation, subclavian vein catheterization, and cardiopulmonary resuscitation Genetic Cystic fibrosis, Ehlers-Danlos syndrome, Marfan syndrome, -1-antitrypsin deficiency associated emphysema, Birt-Hogg-Dub syndrome Hemodynamic Pulmonary Infarction Infectious Necrotizing cavitary lesions (TB, coccidiomycosis), Pneumocystis jirovecii pneumonia, and HIV Inflammatory/immune

Key Facts Terminology

Pneumothorax is defined as presence of air in pleural space

Tension pneumothorax is progressive accumulation of entrapped air within pleural space that results in pressure-induced displacement of mediastinum and heart, resulting in potentially fatal hemodynamic compromise

Etiology

Extensive number of underlying lung diseases, as well as traumatic and iatrogenic injury

Clinical Issues

Differences in presentation and outcome based on whether patient is spontaneously breathing or on mechanical ventilation, with the latter being more

Usual interstitial pneumonia, respiratory bronchiolitis, asthma, hypersensitivity pneumonitis, sarcoidosis, constrictive bronchiolitis following bone marrow transplantation Neoplastic Primary and metastatic pulmonary malignancy, especially when necrotic and cavitary Pleural malignancy: Malignant mesothelioma and metastatic disease Emphysema Paraseptal emphysema with bullae (emphysematous cystic spaces > 1 cm) Other Endometriosis (catamenial pneumothorax), lymphangioleiomyomatosis, Langerhans cell histiocytosis

difficult to recognize and more likely to result in mortality

Macroscopic Pathology

Tracheal deviation, mediastinal shift, and pneumomediastinum

Unilateral lung collapse with positive test for air in pleural space

Signs of prior intervention

Microscopic Pathology

Findings consistent with specific underlying lung disease predisposing to pneumothorax or recent lung injury

Top Differential Diagnoses

Terminal cardiopulmonary resuscitation Simple pneumothorax pneumothorax, because tube may have become kinked or obstructed Symptoms: Ipsilateral pleuritic chest pain, progressive tachycardia, respiratory distress, diaphoresis, hypotension and pallor from hypoxemia, mediastinal shift, and reduced venous return

Organ System Approach to Autopsy: Sudden and Unexpected Death

TENSION PNEUMOTHORAX

Treatment

Early recognition and prompt intervention before hemodynamic deterioration is essential

Hemodynamic improvement is achieved through release of entrapped air, usually by tube thoracostomy

Following decompression, patients are at risk for reexpansion pulmonary edema (REPE) that may further complicate recovery

Prognosis

If untreated, fatal cardiovascular collapse can occur even in healthy, young individuals

CLINICAL ISSUES Presentation

Tension pneumothorax can occur abruptly, but cardiovascular compromise may occur more gradually Incidence of tension pneumothorax varies from ~ 3.5-30% Tension pneumothorax is not uncommon in hospitalized patients, but fatal tension pneumothorax is relatively rare Possibility is expectantly managed in certain patient populations and promptly treated Estimates of missed diagnosis of patients dying in ICU setting range from 1% to almost 4% Missed diagnosis is more likely with ventilation, if cardiopulmonary resuscitation has occurred, or if delay in diagnosis of simple pneumothorax Majority of ventilated patients with pneumothorax will require emergent treatment with tube thoracostomy, given high risk of progression to tension pneumothorax Tension pneumothorax should also be suspected in patients who already have chest tube placed for

As would be expected, mortality is increased in patients with more severe comorbidities who are less able to tolerate hemodynamic compromise and particularly in ventilated patients in ICU setting

IMAGE FINDINGS Radiographic Findings

Tracheal deviation toward opposite side from pneumothorax, flattening of diaphragmatic contour, displaced cardiac silhouette, shifting of left cardiac border

MACROSCOPIC FEATURES General Features

Role of pneumothorax as immediate or contributory cause of death may be difficult to evaluate because of coexistence with other major potentially fatal conditions and because time of onset is often unknown

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Organ System Approach to Autopsy: Sudden and Unexpected Death

TENSION PNEUMOTHORAX Chart review for premortem signs of tension pneumothorax May be more difficult to identify these signs in critically ill, ventilated patients Even if pneumothorax is detected and treated, intervention may not have been sufficient to restore hemodynamic function Forceful terminal CPR may cause tension pneumothorax and should be excluded as a contributing cause of death

With prolonged time interval between pneumothorax

tube

method for distinguishing simple from tension pneumothorax

DIFFERENTIAL DIAGNOSIS

External Examination

Crepitant subcutaneous emphysema Craniofacial congestion secondary to central venous compression

Tracheal deviation toward opposite side of suspected pneumothorax

Signs of intervention such as puncture wound or chest Postmortem radiograph of chest is most sensitive

Internal Examination

Cardiopulmonary Resuscitation (CPR)

Methods to detect pneumothorax prior to opening

A test for air bubbles should be performed bilaterally

body cavities Once thoracic skin is reflected, create pocket of water between reflected skin and rib cage, open pleural cavity under water with scalpel inserted between 2 ribs Air bubbles in the water indicate tension pneumothorax Insert needle attached to syringe filled with water into pleural space (can be inserted through skin before making thoracic skin flap) Air bubbles in water indicate tension pneumothorax Unilateral lung collapse Depression of diaphragm If viewed from abdominal cavity, dome of diaphragm may be displaced downward In severe cases, pneumoperitoneum may be present Pneumomediastinum and mediastinal displacement toward opposite side of suspected pneumothorax Pneumopericardium and cardiac displacement toward opposite side of suspected pneumothorax Look for mechanism of injury Rib fracture with lung puncture wound Bronchopleural fistula If prior chest tube placed, determine that tube is appropriately placed without kinks or obstruction

Correlate clinical events immediately preceding

Organ Examination

underlying lung disease or localized traumatic injury

Histologic Features

and death, characteristic histologic findings may be present Eosinophilic pleuritis Reactive mesothelial hyperplasia Fibrinous exudate Pleural and subpleural parenchymal fibrosis Giant cells consistent with persistent interstitial air Chronic inflammation and hemosiderin deposition Findings that suggest or are consistent with specific underlying lung disease predisposing to pneumothorax Asthma, emphysema, and tuberculosis are some lung diseases that are most frequently associated with pneumothorax

Examine for pleural blebs, bullae, evidence of

MICROSCOPIC PATHOLOGY

Bilateral disease would indicate CPR injury

terminal resuscitation efforts with autopsy findings

Bilateral lung collapse more consistent with vigorous resuscitation than tension pneumothorax Differential for bilateral collapse includes simple pneumothorax on one side and tension pneumothorax on other

Simple Pneumothorax

Diagnosis of tension pneumothorax rests on documentation of unequivocal mediastinal shifting to opposite side If absent, diagnosis defaults to simple pneumothorax

SELECTED REFERENCES 1.

2. 3.

4. 5.

Schneider F et al: Approach to lung biopsies from patients with pneumothorax. Arch Pathol Lab Med. 138(2):257-65, 2014 Yarmus L et al: Pneumothorax in the critically ill patient. Chest. 141(4):1098-105, 2012 Celik B et al: Iatrogenic pneumothorax: etiology, incidence and risk factors. Thorac Cardiovasc Surg. 57(5):286-90, 2009 Leigh-Smith S et al: Tension pneumothorax--time for a rethink? Emerg Med J. 22(1):8-16, 2005 Weissberg D et al: Pneumothorax: experience with 1,199 patients. Chest. 117(5):1279-85, 2000 Barton ED: Tension pneumothorax. Curr Opin Pulm Med. 5(4):269-74, 1999

Gross and Microscopic Features (Left) This photograph demonstrates the waterfilled syringe test for pneumothorax. A needle is attached to a syringe filled with water and is inserted through the thoracic skin into the pleural space. Air bubbles in the syringe indicate a tension pneumothorax. (Right) This view shows a collapsed left lung and chest wall of a patient with metastatic carcinoma and tension pneumothorax. Nodules of metastatic tumor are present on the lung and chest wall .

(Left) Air bubbles in mediastinal soft tissue are consistent with pneumomediastinum in tension pneumothorax. (Right) This patient with severe chronic obstructive pulmonary disease (COPD) and ruptured bulla had tension pneumothorax. The lung is collapsed, and an additional intact bulla is present. Bullae are air-filled spaces beneath the pleura that are usually associated with destruction of lung tissue as seen in emphysema.

Organ System Approach to Autopsy: Sudden and Unexpected Death

TENSION PNEUMOTHORAX

(Left) This is an example of a collapsed left lung secondary to forceful and prolonged CPR. The contralateral lung was adhesed due to prior surgery. Terminal CPR may be associated with a tension pneumothorax that should not be considered a contributory cause of death. (Right) This is a histologic section of bullous paraseptal (distal acinar) emphysema. The bulla is the large airspace in the location. subpleural

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Organ System Approach to Autopsy: Sudden and Unexpected Death

UPPER GASTROINTESTINAL HEMORRHAGE

This peptic ulcer has a characteristic sharply punched out appearance with edges that are level with the surrounding mucosa. Intestinal type tumors tend to rise above surrounding mucosa.

TERMINOLOGY Synonyms

Upper GI bleed

Definitions

Upper gastrointestinal (UGI) hemorrhage: Gastrointestinal hemorrhage that originates proximal to ligament of Treitz Severe; shock, > 6% hematocrit, > 2% hemoglobin, or transfusion of 2 units RBC Hematemesis: Vomiting of blood; almost always associated with hemorrhage from esophagus, stomach, or duodenum Bright red blood: Recent hemorrhage "Coffee grounds": Result of gastric acid effect on blood Melena: Black, tarry stool usually due to UGI hemorrhage but may be seen with bleeding as far down as cecum Result of digestive action by GI tract and bacteria on blood Hematochezia: Bright red blood in stool; typically result of lower GI hemorrhage but can be seen with large, rapid UGI bleed

This H&E section from the stomach shows chronic gastritis and mucosal erosion. The patient had a history of NSAID use, and a special stain for Helicobacter was negative.

Aspirin/NSAIDs: Used by 11% of adults; causes mucosal injury in part by inhibiting production of protective prostaglandins Predictors of poor outcome: Age > 60, onset while inpatient, comorbid conditions, shock/orthostasis, coagulopathy, multiple transfusions, endoscopically visible vessel, or arterial bleeding Complications of PUD: Potentially life threatening; unusual because of effective medical therapy Perforation: Ulcer erodes through free wall of stomach or duodenum with bleeding and peritonitis Penetration: Ulcer erodes into adjacent structures Obstruction: Chronic gastroduodenitis leads to fibrosis and stenosis of gastric outlet Excess acid production Gastrinoma (Zollinger-Ellison syndrome): Endocrine tumors, usually pancreatic; may cause multiple ulcers or ulcers in unusual locations Mast cell tumors: Produce high levels of histamine (potent stimulator of gastric acid secretion)

Esophageal Varices

2nd most common cause of significant UGI bleeding

Result of portal hypertension, usually in setting of hepatic cirrhosis

ETIOLOGY/PATHOGENESIS Peptic Ulcer Disease (PUD)

Most common cause of significant UGI bleeding Acid-induced injury to damaged gastric or duodenal

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mucosa Mucosal injury Helicobacter pylori: Colonizes mucous layer of stomach with resulting inflammation and mucosal injury Most frequent cause of duodenal ulcers

Clinical: 30% mortality with each episode of bleeding

Hematemesis with potentially massive blood loss Prognosis depends in part on severity of underlying hepatic disease

Mallory-Weiss Tear

Etiology: Sudden increases in intraabdominal pressure with transmural pressure gradient across distal esophagus; often associated with hiatal hernia Severe vomiting, retching, coughing, straining; rarely reported with hiccups, CPR, trauma, convulsions

Key Facts Etiology

Predictors of poor outcome: Age > 60, onset while inpatient, comorbid conditions, shock/orthostasis, coagulopathy, multiple transfusions, endoscopically visible vessel, or arterial bleedings

Top Differential Diagnoses

Eversion of unopened esophagus is a simple means of demonstrating esophageal varices UGI tumors (primary and metastatic): 7% of UGI hemorrhage Usually in late-stage disease Poor prognosis

Peptic ulcer disease: Most common cause of severe

Diagnostic Checklist

UGI hemorrhage Typical gross appearance: Sharply punched-out gastric or duodenal ulcers with nonraised edges and clean ulcer base Histology is crucial to exclude malignancy Esophageal varices: 2nd most common cause of severe UGI hemorrhage Esophageal varices collapse after death and are notoriously difficult to demonstrate

Clinical presentation, age, and premortem diagnostic studies should guide dissection Other significant history of (NSAID use, gastritis, cirrhosis, trauma, aortic surgery, etc.) may lead to index of suspicion Acuity and volume of blood influence the differential diagnosis

Clinical: Typical presentation is retching and vomiting followed by hematemesis (often painless) Blood loss is usually small, and episode is selflimited (90%) Most of these lesions will resolve spontaneously within 48 hours 10% will have severe UGI bleed

Tumors

Primary (epithelial, stromal, lymphoid) and metastatic (melanoma, carcinoma, etc.) UGI tumors can cause significant UGI bleeding Oncology patients can also have bleeding from PUD, varices, or other nonneoplastic causes UGI bleeding is usually a complication of late-stage disease and carries poor prognosis

Aortoduodenal Fistula

Rare and easily missed cause of catastrophic UGI

Gross findings may be subtle

Typically older patients; striking female preponderance Associated with portal hypertension in 30% of cases but is also seen with systemic sclerosis and a number of other conditions Portal hypertensive gastropathy Seen exclusively in patients with portal hypertension; can sometimes cause chronic hemorrhage and anemia Dieulafoy lesion (caliber-persistent artery): Thought to result from congenital vascular malformation Bleeding is typically self-limited but may be severe; can cause recurrent hemorrhage Cameron lesion: Ulcers that arise in ~ 5% of hiatal hernias Most will be asymptomatic but some will cause chronic hemorrhage; rare cases of acute UGI hemorrhage are reported

Organ System Approach to Autopsy: Sudden and Unexpected Death

UPPER GASTROINTESTINAL HEMORRHAGE

bleeding

Typically between aneurysmal abdominal aorta and 3rd portion of duodenum May be preceded by a small UGI bleed (herald bleed) Aortoenteric fistulas may rarely result from swallowed sharp objects (needles, pins, swizzle sticks) and arise elsewhere in GI tract (e.g., aortoesophageal fistula)

Hematobilia

Rare cause of UGI hemorrhage Abnormal communication between biliary tree and blood vessels

Can result from trauma, iatrogenic injury, cholecystitis, bile duct tumors, or arterial aneurysms Hemosuccus pancreaticus Bleeding through pancreatic duct into ampulla of Vater

Other Vascular Lesions

Gastric antral vascular ectasia

Uncommon cause of chronic UGI hemorrhage and anemia

MACROSCOPIC FEATURES Peptic Ulcer

Sharply punched-out ulcers without raised edges in stomach/duodenum Gross features can overlap, but carcinomas usually have raised edges Clean ulcer base "Coffee ground" gastric contents

Esophageal Varices

External examination: Stigmata of portal hypertension Jaundice, caput medusa, spider angiomata

Internal examination: Changes of portal hypertension Cirrhosis, splenomegaly, ascites

Esophagus: Varices collapse after death and are notoriously hard to demonstrate Technique: Open stomach along greater curvature, leave esophagus unopened, tie off proximal end of esophagus, use a clamp to reach up the esophageal lumen, grasp proximal end, and evert esophagus

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Organ System Approach to Autopsy: Sudden and Unexpected Death

UPPER GASTROINTESTINAL HEMORRHAGE

Causes of Upper Gastrointestinal Hemorrhage Cause

Frequency

Peptic ulcer disease*

38%

Esophageal varices*

16%

Esophagitis

13%

Unknown

Upper gastrointestinal tumors (primary and metastatic)

Angioma

Mallory-Weiss Tear

Other

Percentages based on a clinical series. Other causes include mucosal erosion, Dieulafoy lesions, Cameron lesions, aortoduodenal fistula, hemobilia, hemosuccus pancreaticus, gastric antral vascular ectasia, and UGI involvement by amyloidosis. *Most common causes of fatal UGI hemorrhage

Mallory-Weiss Tear

defect in mucosa and submucosa proximal stomach

Tumors

Primary intestinal-type gastric tumors

Polypoid or fungating tumors with central ulceration Ulcerated: Gross features can overlap with peptic ulcers Nodular, shaggy, necrotic ulcer base Diffuse-type gastric carcinoma (linitis plastica): Rarely presents with bleeding

Primary: Fistula between abdominal aortic aneurysm and duodenum

Secondary: Fistula between surgically repaired aorta and duodenum; usually 3-5 years postoperatively

Hematobilia/Hemosuccus Pancreaticus

Pancreatic tumor or pseudocyst erodes into vessel (difficult to demonstrate at autopsy)

Affected vessel often aneurysmal

Other Vascular Lesions

Gastric antral vascular ectasia: 2 patterns

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Most arise in distal neck of hiatal hernia Small, linear, erythematous erosions

Distal esophagus with occasional extension into

Aortoduodenal Fistula

Cameron lesions

Usually single (rarely multiple), linear, longitudinal

"Watermelon" stomach: Submucosal vascular ectasia with erythematous mucosal crests in parallel linear pattern Diffuse antral mucosal spots separated by grossly normal mucosa Often seen with portal hypertension Portal hypertensive gastropathy Mosaic or "snakeskin" appearance seen endoscopically Beefy red mucosa with petechiae, erosions, and ulcers Dieulafoy lesion Usually single lesion in distal esophagus/proximal stomach within 5 cm of GEJ (can be seen elsewhere) Typically small (0.2-0.5 cm) mucosal defect Easily missed; requires careful inspection of esophageal and gastric mucosa

MICROSCOPIC PATHOLOGY Peptic Ulcer Disease

Ulceration and acute and chronic gastroduodenitis Helicobacter easier to see with histochemical stains or immunoperoxidase

Esophageal Varices

Dilated submucosal vessels

Other Vascular Lesions

Gastric antral vascular ectasia

Dilated submucosal vessels with fibrohyalinosis and thrombosis Portal hypertensive gastropathy Dilated mucosal and submucosal veins and capillaries Dieulafoy lesion (caliber-persistent artery) Single, dilated (0.1-0.5 cm) muscular artery under a small mucosal erosion Muscular artery histologically unremarkable, but larger than surrounding mucosal vessels Cameron lesions Histologic changes resemble those of ischemic gastritis Clinical/endoscopic information is essential

SELECTED REFERENCES 1. 2.

4. 5.

Feinman M et al: Upper gastrointestinal bleeding. Surg Clin North Am. 94(1):43-53, 2014 Kapadia S et al: Cameron ulcers: an atypical source for a massive upper gastrointestinal bleed. World J Gastroenterol. 18(35):4959-61, 2012 Fenoglio-Preiser CM et al: Gastrointestinal Pathology: An Atlas and Text. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2008 Merrell SW et al: Hemobilia--evolution of current diagnosis and treatment. West J Med. 155(6):621-5, 1991 Clay RP et al: Hemosuccus pancreaticus. An unusual cause of upper gastrointestinal bleeding. Ann Surg. 202(1):75-9, 1985 Zimmerman MR: Postmortem demonstration of esophageal varices. Am J Clin Pathol. 65(5):729, 1976

Gross and Microscopic Features (Left) This image shows the mucosal surface of an unopened, everted esophagus from a patient with cirrhosis and portal hypertension. Flaccid, dilated submucosal vessels can be seen. During life, these vessels would be visible endoscopically as distended esophageal varices. (Right) This stomach image shows the beefy red mucosa, punctate erythema, and focal ulceration characteristic of portal hypertensive gastropathy. The patient also had cirrhosis and splenomegaly.

(Left) This image shows a section through the duodenum and pancreas from a case of penetrating duodenal ulcer. The ulcer , which extends through the full thickness of the duodenum and into the adjacent pancreas, resulted in fatal hemorrhage (Right) H&E section of a penetrating duodenal ulcer shows the pancreatic tissue in the ulcer bed. With effective medical therapy, complications of peptic ulcer disease (perforation, penetration, and obstruction) have become unusual.

Organ System Approach to Autopsy: Sudden and Unexpected Death

UPPER GASTROINTESTINAL HEMORRHAGE

(Left) In situ photograph of a perforated gastric ulcer shows a sharply punched out, full-thickness ulcer with surrounding serositis and evidence of fat necrosis. (Right) This image of an unopened, everted esophagus shows a single linear, longitudinal defect that involves the mucosa and submucosa of the distal esophagus, features characteristic of a MalloryWeiss tear. This patient had prolonged severe vomiting followed by hematemesis.

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Organ System Approach to Autopsy: Sudden and Unexpected Death

LOWER GASTROINTESTINAL HEMORRHAGE

This large rectosigmoid adenocarcinoma with rolled, heaped-up edges has a central ulcer and hemorrhagic foci.

TERMINOLOGY Synonyms

Lower gastrointestinal bleed (LGIB)

Definitions

Lower GI hemorrhage

Traditional: Blood loss from GI tract distal to ligament of Treitz Current: Blood loss from colon or anorectum Hematochezia: Bright red blood upon defecation Melena: Black tarry stool due to breakdown of hemoglobin Occult bleed: Slow, chronic bleeding not seen grossly

ETIOLOGY/PATHOGENESIS Common Causes Diverticular disease

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30-40% of LGIB in adults, incidence in elderly Most commonly in left colon Acquired pseudodiverticula Herniation through defect in muscularis Contains mucosa and submucosa only Meckel diverticulum Common cause of LGIB in children Congenital true diverticulum (all layers of bowel wall) in ileum Ischemic enterocolitis Nonocclusive: Low blood flow, vasospasm, medications/drugs Occlusive: Atherosclerosis, thromboembolic, vasculitis External: Volvulus, tumor, intussusception, obstruction Stercoral ulcer Rectosigmoid ulcer due to stool impaction in elderly Angiodysplasia

This portion of small bowel shows an area of ischemic enteritis with a discrete, well-demarcated segment of dark red-purple hemorrhagic mucosa .

Acquired vascular lesion in elderly, usually right colon Arteriovenous malformation Developmental vascular defect in small/large bowel Neoplasia Benign polyps > 1 cm may bleed from surface erosion Postpolypectomy bleeding may occur up to 2 weeks after procedure Incidence is 1-6%, results from inadequate hemostasis, risk with size of polyp Carcinomas usually cause occult-type bleeding Hematochezia may occur with distal tumors Anorectal disease Hemorrhoids Cushions of fibrovascular tissue (engorged veins) thrombosis Bleeding may occur due to prolapse or sphincter or intraabdominal pressure Radiation-induced proctitis/colitis Consequence of irradiation for pelvic malignancies Mucosal/rectal prolapse Due to abnormal pelvic floor muscle function during defecation causing excessive straining Other inflammatory diseases Inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn disease), usually bloody diarrhea (severe LGIB < 1%) Medications (e.g., NSAIDs, sodium polystyrene) Infections Bloody diarrhea/dysentery (enterohemorrhagic Escherichia coli, Salmonella, Shigella) Pseudomembranous (Clostridium difficile) Ulcerative (viral, Entamoeba histolytica) IBD-like (Yersinia)

Key Facts Terminology

Lower GI hemorrhage

Traditional: Blood loss from GI tract distal to ligament of Treitz Recent: Blood loss from colon or anorectum

Etiology

Diverticular disease Infections

Clinical Issues

LGIB accounts for 20% of all GI bleeding Exact location of bleed not identified clinically in 10% of cases

Important elements of chart review

Type of bleeding, frequency, severity, duration Factors affecting coagulation (cirrhosis, medications) Medications (NSAIDs, sodium polystyrene) Underlying GI disease Prior therapy

Bloody diarrhea/dysentery (enterohemorrhagic E. coli, Salmonella, Shigella) Pseudomembranous (C. difficile) Ulcerative (viral, E. histolytica) IBD-like (Yersinia) IBD (ulcerative colitis, Crohn disease), usually bloody diarrhea (severe LGIB < 1%)

Top Differential Diagnoses

CLINICAL ISSUES

IMAGE FINDINGS

Epidemiology

CT Findings

Incidence

20-30 cases/100,000 adults in US 20% of all GI bleeds are LGIB Exact location of bleed not identified clinically in 10% of cases

Presentation

Hematochezia, melena, occult bleed, anemia, abdominal pain Important elements of chart review Type of bleeding, frequency, severity, duration Factors affecting coagulation (cirrhosis, medications) Medications (NSAIDs, sodium polystyrene) Underlying GI disease Diverticular disease, neoplasm, IBD Prior therapy Radiation, endoscopic biopsy/clips/cautery/ injection, angiographic embolization/vasopressin infusion

Laboratory Tests

hemoglobin/hematocrit, iron deficiency anemia Thrombocytopenia, prothrombin & partial thromboplastin times (+) fecal occult blood test, stool bacteria cultures, ova and parasite tests, C. difficile toxin assay, blood cultures

Prognosis

Mortality 5% but if bleeding occurs after hospitalization

morbidity in older patients Spontaneous cessation in 80% of cases May vary with etiology

Stercoral ulcer: High risk of perforation Meckel diverticulum: Intussusception or volvulus Angiodysplasia: May cause massive hemorrhage

Postmortem autolysis occurs rapidly in luminal GI tract, may obscure diagnostic features of some diseases

Thickened bowel wall, edema, pericolonic stranding, obstruction, mass, diverticula

Nuclear Medicine Findings

Organ System Approach to Autopsy: Sudden and Unexpected Death

LOWER GASTROINTESTINAL HEMORRHAGE

CT angiography or nuclear scintigraphy/RBC scan may localize bleed

MACROSCOPIC FEATURES External Examination

Pallor of skin, mucous membranes, conjunctiva Koilonychia, oral ulcers, glossitis External hemorrhoids, perianal ulcers/fissures, hernias

Internal Examination

Ascites, hemoperitoneum, perforations peritonitis, adhesions, strictures

Surgical anastomoses: Ulcers, ischemia, perforation, dehiscence

Organ Examination Diverticular disease

Outpouchings of mucosa through muscularis propria (pseudodiverticula), strictures, subserosal abscess cavities, perforation Meckel diverticulum Outpouching of bowel wall along antimesenteric border of ileum Ischemic enterocolitis Segmental vs. diffuse, watershed areas (splenic flexure, rectosigmoid junction) Mucosal congestion, edema, ulceration perforation, serosal fibrinous exudate, pseudomembranes, gross thrombi in mesenteric vessels Benign ulcers (stercoral, medication induced) Hemorrhagic mucosa and ulcer with purulent exudate

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Organ System Approach to Autopsy: Sudden and Unexpected Death

LOWER GASTROINTESTINAL HEMORRHAGE Angiodysplasia

Gross appearance usually subtle, appears as foci of mucosal/submucosal erythema Arteriovenous malformation Mass of tortuous dilated vessels usually in subserosa Neoplasia Polyp or mass with surface erosion/ulcer Following polypectomy or biopsy of mass: Hemorrhagic biopsy site mucosal defect Anorectal disease Hemorrhoids Dilated, engorged submucosal vessels ulceration, thrombosis Radiation-induced proctitis/colitis Acute: Friable mucosa with erosions and edema Chronic: Result of vascular injury & ischemia (ulcers, mucosal telangiectasias, strictures, fistulas, serosal adhesions) Mucosal/rectal prolapse Well-demarcated ulcers, polypoid erythematous mass-like lesions Other inflammatory diseases Ulcerative colitis: Diffuse continuous hemorrhagic granular mucosa from rectum proximally, ulcers Crohn disease: Patchy involvement of small large bowel by deep ulcers, cobblestone mucosa, creeping fat, strictures, fistulas, usually rectal sparing Infections: Variable, typically diffuse erythema

Sections to Be Submitted

Gross mucosal abnormalities, ulcers, perforations Mesenteric vessels in cases of ischemia (emboli, thrombosis) Large polyps/masses + grossly positive lymph nodes

Subserosal clusters of dilated arteries and veins with arterialization of veins (thickened wall with myointimal hyperplasia) Radiation proctitis/colitis Acute: Erosions, submucosal edema, regenerative epithelial changes Chronic: Ulcers, dilated mucosal capillaries, hyalinized lamina propria and submucosal vessels, atypical fibroblasts Mucosal/rectal prolapse Mucosal erosion, vascular congestion, distorted and dilated crypts, lamina propria fibrosis Thickened muscularis mucosa with splayed muscle fibers extending up into mucosa Inflammatory bowel disease Ulcerative colitis: Chronic active colitis ulcers affecting mucosa only Crohn disease: Chronic active colitis/enteritis ulcers and granulomas, transmural inflammation

ANCILLARY TESTS Microbiology

Stool cultures and other tests (ova and parasites, PCR, etc.) can be performed on postmortem samples

Blood cultures in suspected infection/sepsis

DIFFERENTIAL DIAGNOSIS Autolysis

Occurs rapidly post mortem Affects mucosa first with fading of histologic detail, loss of epithelial cells, ghosts of normal structures May mimic ischemic colitis, but lack of vital reaction and vascular thrombosis helps to distinguish May obscure diagnostic features of other diseases

MICROSCOPIC PATHOLOGY Histologic Features Diverticular disease

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Peridiverticular abscess, foreign body giant cell reaction, cryptitis, congestion, erosion with hemorrhage Meckel diverticulum All 3 layers of bowel wall, ileal-type epithelium various heterotopias Ischemic enterocolitis Early: Submucosal edema, congestion, hemorrhage Ulcers, mucopurulent exudate (pseudomembranes), loss of epithelium, mucosal/transmural necrosis Remaining crypts have withered appearance with hyalinized lamina propria Mesenteric vessels organizing thrombi, atherosclerosis, cholesterol emboli, vasculitis Benign ulcers (stercoral, medication induced) Erosions, nonspecific inflammation, fibrinopurulent exudate, deep ulcers with hemorrhage Angiodysplasia Submucosal cluster of dilated thin-walled veins, arterioles, capillaries Arteriovenous malformation

REPORTING CONSIDERATIONS Key Elements to Report

Location and etiology of hemorrhage

Cause of death, contributing factor, or incidental

Underlying GI disease and risk factors for hemorrhage Effects of hemorrhage/disease on other organs

SELECTED REFERENCES 1.

Barnert J et al: Diagnosis and management of lower gastrointestinal bleeding. Nat Rev Gastroenterol Hepatol. 6(11):637-46, 2009 West A.B. et al: Vascular disorders of the GI tract. In R.D. Odz et al: Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 2nd ed. Philadelphia: Saunders/ Elsevier. 185-230, 2009 Edelman DA et al: Lower gastrointestinal bleeding: a review. Surg Endosc. 21(4):514-20, 2007

Gross and Microscopic Features (Left) This is a cross section of a diverticulum in the sigmoid colon showing outpouching of the mucosa through the muscularis propria with a peridiverticular abscess cavity and associated fibrosis . (Right) The entire colonic mucosa is diffusely hemorrhagic and granular with numerous irregular ulcers in this patient with ulcerative colitis.

(Left) This example of rectal prolapse shows polypoid mucosa with surface erosion and ischemic-type injury , exposed mucosal capillaries , and splayed muscularis mucosa with smooth muscle fibers extending vertically toward the lumen . (Right) The mucosa in this NSAID-associated cecal ulcer is completely eroded, exposing a large submucosal vessel . Submucosal acute inflammation and necrosis and purulent exudate within the lumen are also present.

(Left) This case of ischemic enteritis shows complete epithelial loss and "ghosts" of villi . Full-thickness coagulative necrosis , hemorrhage, and transmural acute inflammation are also present. (Right) Autolyzed small bowel with near total epithelial loss and "ghosts" of villi mimics ischemic enteritis. Basal crypt epithelial cells are preserved . The muscularis propria is intact and viable without evidence of transmural hemorrhage, necrosis, or inflammation.

Organ System Approach to Autopsy: Sudden and Unexpected Death

LOWER GASTROINTESTINAL HEMORRHAGE

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Organ System Approach to Autopsy: Sudden and Unexpected Death

INTESTINAL ISCHEMIA

This segment of infarcted small bowel with a red-black hemorrhagic appearance was due to mesenteric vein thrombosis in a hypercoagulable patient with portal vein thrombosis and pulmonary embolism.

TERMINOLOGY Definitions

Reduction in intestinal blood flow resulting in bowel injury infarction, necrosis, and perforation

Histologic sections of the infarcted small bowel show transmural hemorrhage , vascular congestion , and mucosal necrosis .

hypertension, periportal malignancy, pancreatitis, severe dehydration Secondary to mechanical obstruction Strangulated hernia, intussusception, volvulus, tumors, adhesions

Chronic Mesenteric Ischemia (CMI)

ETIOLOGY/PATHOGENESIS Acute Mesenteric Ischemia (AMI) Mesenteric artery embolism

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50% of AMI cases Usually involves superior mesenteric artery (SMA) SMA anatomy risk for obstruction: High basal flow rate and acute angle of take-off from aorta Risk factors: Atrial fibrillation, other arrhythmia, myocardial infarction, valvular disease, endocarditis, cardiac catheterization Mesenteric artery thrombosis 15-25% of AMI, usually at SMA origin or celiac axis Usually thrombosis superimposed on a critical atherosclerotic lesion Less common: Vasculitis, SMA aneurysm/dissection, thrombophilia, fibromuscular dysplasia, vascular amyloid Nonocclusive mesenteric ischemia (NOMI) 20-30% of AMI, many etiologies all vasoconstriction of intestinal vessels and flow Risk factors: Cardiogenic, hypovolemic, or septic shock, congestive heart failure, cardiac/major abdominal surgery, vasoconstricting drugs (e.g., digoxin, -adrenergic agonists, cocaine, ergot) Mesenteric venous thrombosis 5% of AMI cases, impaired venous return, bowel wall edema, impaired microvascular perfusion, arterial flow, and hemorrhage Risk factors: Inherited or acquired hypercoagulable states, abdominal infections/trauma, portal

Rare due to rich collateral networks

Need to have 2 mesenteric arterial branches involved by atherosclerosis/stenosis to occur F > M, 50-60 years; associated with systemic atherosclerosis, coronary artery disease, tobacco use, and hypertension

Ischemic Colitis

Specific occluding lesion rarely identified, may be transient and reversible or chronic

Usually acutely blood flow

"Watershed" areas with limited collateral flow vulnerable (i.e., splenic flexure, right colon, rectosigmoid junction) Risk factors: Hypotension/shock, hypercoagulable states, mechanical obstruction (adhesions, diverticulitis, prolapse, tumors, volvulus), aortoiliac or cardiac bypass surgery Drugs/medications: Antihypertensives, cocaine, sodium polystyrene (Kayexalate), oral contraceptives, digoxin, nonsteroidals, diuretics, pseudoephedrine Infectious ischemic-type colitis (e.g., Escherichia coli 0157:H7, Clostridium difficile [C. diff], Salmonella, Shigella, Entamoeba histolytica)

CLINICAL ISSUES Presentation

Abdominal pain (out of proportion to physical exam findings in AMI), nausea, vomiting, diarrhea, hematochezia, melena

Key Facts Terminology

Reduction in intestinal blood flow resulting in bowel injury infarction, necrosis, and perforation

Examine aorta and branches for atherosclerosis, stenosis/occlusion, thrombi, status of stents

Examine branches of inferior vena cava for thrombi

Etiology

Microscopic Pathology

Macroscopic Pathology

of cytoplasmic mucin and hyperchromatic nuclei, sloughing, necrosis, ulcers Submucosal edema, congestion, lamina propria hemorrhage, transmural necrosis/hemorrhage, serositis Vascular findings: Thromboemboli, cholesterol emboli, atherosclerosis, vasculitis, amyloid deposition, tumor thrombi, pyelophlebitis

Mesenteric artery embolism Mesenteric artery thrombosis Nonocclusive mesenteric ischemia (NOMI) Mesenteric venous thrombosis Secondary to mechanical obstruction Ischemic colitis Drugs, infections Evaluate small and large intestine in situ for perforations, adhesions, volvulus, strangulated hernias, intussusception, masses

Weight loss, postprandial pain, early satiety, and food aversion (CMI) Tachycardia, tachypnea, arrhythmia, altered mental status, fever, anorexia, abdominal tenderness, peritoneal signs (late), shock Indirect signs of atherosclerosis ( peripheral pulses, carotid/femoral bruits, stigmata of prior stroke) Important elements of chart review General risk factors: Older age, tobacco use, hypertension, thrombophilia, obesity ( risk for venous thrombi), dyslipidemia Cardiac risk factors: Myocardial infarction, arrhythmia, cardiac valve disease endocarditis (nonbacterial thrombotic or infectious), congestive heart failure, known aneurysm (heart, aorta) Prior procedures: Cardiac catheterization, cardiac/ abdominal surgery, arterial bypass surgery Medications/drugs, history of malignancy or cirrhosis Surgical/other interventions performed, postintervention course

Laboratory Tests

Hemoconcentration, leukocytosis, metabolic acidosis with anion gap amylase, lactate dehydrogenase, alkaline phosphatase digoxin level, (+) cocaine metabolites (+) fecal occult blood, blood culture, stool culture/C. diff toxin assay/parasites

Prognosis

Mortality varies depending on cause

Mesenteric artery embolus ~ 70% Mesenteric artery thrombosis ~ 90% NOMI ~ 70-90% Mesenteric venous thrombosis ~ 20-50% Ischemic colitis (if gangrenous) ~ 50%

Complications

Ileus, perforation, peritonitis, gastrointestinal bleeding, sepsis, multiorgan failure

Epithelial degenerative/reactive changes with loss

Top Differential Diagnoses Autolysis

IMAGE FINDINGS Ultrasonographic Findings

Arterial occlusion/stenosis (with Doppler)

CT Findings

Segmental circumferential bowel wall thickening,

Organ System Approach to Autopsy: Sudden and Unexpected Death

INTESTINAL ISCHEMIA

mesenteric stranding/edema, vascular occlusions, atherosclerosis, pneumatosis, portal venous gas Masses/obstructions, volvulus, intussusception Ascites, intraabdominal free air

Mesenteric Angiography

Diagnostic and therapeutic (not typically used for ischemic colitis)

MACROSCOPIC FEATURES External Examination

Surgical interventions: Wound status, drains Abdominal/inguinal/incisional hernias Sepsis changes: Petechiae, jaundice, acrocyanosis

Internal Examination

Ascites feculent debris Peritonitis (green fibrinous exudates on peritoneal/ serosal surfaces), adhesions, masses

Evaluate small and large intestine in situ for perforations, adhesions, volvulus, strangulated hernias, intussusception, masses

Organ Examination

Examine aorta and major branches for atherosclerosis, aneurysms, dissection, stenosis/occlusion, thrombi, presence and status of stents Examine for evidence of thrombophilia and presence of venous thrombi/thromboemboli Inferior vena cava thrombi, presence and status of previously inserted IVC filter Portal vein thrombosis Pulmonary artery venous thromboembolism

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Organ System Approach to Autopsy: Sudden and Unexpected Death

INTESTINAL ISCHEMIA Legs can be "milked" for evaluation of deep vein thrombosis once organs are removed Small and large intestine Early/acute ischemia Friable, erythematous mucosa ulcers, pseudomembranes Thickened edematous or thin friable bowel wall, pneumatosis (submucosal/subserosal bubbles/ cystic nodules), perforation Red/black hemorrhagic mucosa and boggy hemorrhagic wall (usually in venous insufficiency) Chronic ischemia Circumferential bowel wall thickening, strictures Segmental, patchy, or diffuse involvement Mesenteric/subserosal vessels: Thrombi, atherosclerotic lesions, stenosis Lungs: Edema, congestion, infection (pneumonia may be possible source of septic shock ischemic bowel) Liver: Congestion/necrosis (shock), cholestasis (sepsis), portal vein thrombosis Kidneys: Cortical pallor, medullary congestion Heart and vasculature Atherosclerotic coronary and aortic disease myocardial acute/chronic ischemia Check for vascular thrombi, dissection, aneurysm Thromboembolic foci Atrial/ventricular thrombi (also check for patent foramen ovale paradoxical embolization venous to arterial), vegetations on valves (thrombotic or endocarditis), neoplasms (rare: Atrial myxoma, papillary fibroelastoma of aortic valve)

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ANCILLARY TESTS Microbiology

Blood, fluid collection, stool cultures, and other stool studies (e.g., ova and parasites, toxin assays) can be performed postmortem Gram/fungal stains on possible infected vegetations, other areas of suppurative inflammation

MICROSCOPIC PATHOLOGY

DIFFERENTIAL DIAGNOSIS

Histologic Features

Autolysis

Small and large intestine

Shock changes: Centrilobular/perivenular congestion hepatocellular necrosis Lungs: Bronchopneumonia, diffuse alveolar damage (alveolar hyaline membranes, neutrophils, fibrin deposition, edema), thromboemboli, intraalveolar hemorrhage Kidneys Dilated tubules and tubal epithelial necrosis/ sloughing (acute tubular injury), coagulative necrosis of cortex (cortical necrosis) Arteriolosclerosis, glomerular capillary thrombi (disseminated intravascular coagulation from sepsis) Heart Subendocardial/myocardial contraction band injury, coagulative necrosis, edema, hemorrhage, scarred thinned aneurysm wall usually with mural thrombus Nonbacterial thrombotic endocarditis (bland [noninfected] thrombi along closing edge of valve), infected vegetation with fibrin, scattered leukocytes, bacterial/fungal colonies

Early/acute ischemia Epithelial degenerative/reactive changes with loss of cytoplasmic mucin and hyperchromatic nuclei, sloughing, necrosis Ulcers, fibrinopurulent exudate Submucosal edema, congestion, lamina propria hemorrhage, transmural necrosis/hemorrhage, acute/organizing serositis Remaining crypts are "withered" Pneumatosis: Cystic spaces lined by macrophages and multinucleated giant cells Chronic ischemia Fibrosis of all layers of bowel wall ulcers Vascular findings: Thromboemboli, cholesterol emboli, atherosclerotic changes, vasculitis, amyloid deposition (Congo red stain [+]), tumor thrombi, pyelophlebitis Sodium polystyrene (Kayexalate) crystals: Nonpolarizable, basophilic crystals with fish scale or mosaic appearance present in ulcer exudate Liver Sepsis changes: Hepatocellular, canalicular, and ductular cholestasis

Occurs rapidly postmortem Affects mucosa first with fading of histologic detail, loss of epithelial cells, ghosts of normal structures

Lack of vital reaction (hemorrhage, inflammation, necrosis) or vascular thrombosis

REPORTING CONSIDERATIONS Key Elements to Report

Immediate cause of death and how it relates to intestinal ischemia

Etiology of intestinal ischemia and subsequent complications

Underlying conditions association with development of intestinal ischemia

SELECTED REFERENCES 1. 2. 3.

Bobadilla JL: Mesenteric ischemia. Surg Clin North Am. 93(4):925-40, ix, 2013 Byard RW: Acute mesenteric ischaemia and unexpected death. J Forensic Leg Med. 19(4):185-90, 2012 Florian A et al: Mesenteric ischemia--a complex disease requiring an interdisciplinary approach. A review of the current literature. Rom J Intern Med. 48(3):207-22, 2010 Harnik IG et al: Mesenteric venous thrombosis. Vasc Med. 15(5):407-18, 2010

Gross and Microscopic Features (Left) This segment of small bowel from a patient with multiple abdominal adhesions shows patchy redblack mucosal discoloration in areas of ischemic injury. (Right) Acute peritonitis and serositis developed in a patient with ischemic colitis due to multiple hypotensive episodes that resulted in rectosigmoid perforation and sepsis.

(Left) This section of normal colon shows changes of autolysis without evidence of injury. The surface epithelium has faded with loss of epithelial cells in crypts . The submucosa, muscularis propria, and subserosa are intact . (Right) Although the mucosa is autolyzed, ischemic colitis can still be diagnosed by the presence of a "vital reaction" in the tissue (i.e., lamina propria hemorrhage , transmural inflammation , and vascular congestion ).

Organ System Approach to Autopsy: Sudden and Unexpected Death

INTESTINAL ISCHEMIA

(Left) This segment of colon has an erythematous, granular mucosa with multiple tan-brown ulcers in this case of ischemic colitis due to sodium polystyrene use in a patient with chronic kidney failure. (Right) Sodium polystyrene crystals (basophilic with a mosaic or fish scale appearance) are present in the fibrinopurulent ulcer exudate in this patient with ischemic colitis.

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Organ System Approach to Autopsy: Sudden and Unexpected Death

HEPATIC HEMORRHAGE

The cut surface of this hepatocellular carcinoma shows intratumoral hemorrhage/hematoma .

TERMINOLOGY Definitions

Intraparenchymal with hematoma hemobilia or hepatic rupture with hemoperitoneum

ETIOLOGY/PATHOGENESIS Tumors

Pathogenesis of rupture

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intravascular/intratumoral pressure resulting from thrombi venous outflow obstruction, vascular rupture and intratumoral/intraparenchymal hemorrhage Direct pressure of tumor on capsule, extrahepatic invasion Hepatocellular carcinoma Rupture in 3-26% Risk factors for rupture: Cirrhosis, hypertension, size > 5 cm, protrusion from surface, vascular thrombi, extrahepatic invasion Hepatocellular adenoma 4 major subtypes: HNF1A mutated type (steatotic), -catenin mutated type, inflammatory (a.k.a. telangiectatic) type, unclassified type (no mutations or specific features) Rupture in up to 25% Risk factors for rupture: Size > 5 cm, recent hormone use or pregnancy, inflammatory type due to presence of sinusoidal dilatation/peliosis Hemangioma Rupture in 1-4% Risk factors for rupture: Large size, coagulopathy Metastatic neoplasms Rupture is rare; exact incidence unknown Risk factors for rupture: Large size, subcapsular location Other rare primary hepatic tumors

A histologic section of this hepatocellular carcinoma shows sheets of malignant hepatocytes with intratumoral hemorrhage/hematoma .

Benign cysts/polycystic liver disease, angiosarcoma, epithelioid hemangioendothelioma

Pregnancy Related

Rupture in ~ 1-2% with severe preeclampsia/eclampsia hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome Usually multiparous, 30-40 years old Exact cause unknown; hypotheses include hypertension, hemolysis, vasospasm fibrin deposition, ischemia, infarction, sinusoidal obstruction, neovascularization microhemorrhage, hematoma, rupture

Iatrogenic

Status post percutaneous biliary drain placement

Incidence of significant hemorrhage is ~ 2-3% Causes: Injury to hepatic artery, portal vein, or intercostal artery resulting in (peri)hepatic or gastrointestinal hemorrhage, bleeding into biliary drain, or hemothorax Status post core biopsy Incidence of significant hemorrhage is ~ 0.3-0.5% Risk factors for hemorrhage: age, cirrhosis, > 3 passes performed Early/immediate hemorrhage due to capsular laceration or vascular injury Delayed hemorrhage (days after biopsy) from pseudoaneurysm formation Status post cholecystectomy Incidence of postoperative hemorrhage is ~ 0.1-0.2% Causes: Parenchymal injury to gallbladder bed, puncture of liver with trocar, capsular tears from traction Status post transjugular intrahepatic portosystemic shunt (TIPS) procedure Incidence of significant hemorrhage is < 1% Causes: Capsular laceration during venogram for portal vein localization, portal vein perforation while obtaining portal vein access, inferior vena

Key Facts Terminology

Intraparenchymal with hematoma hemobilia or hepatic rupture with hemoperitoneum

Clinical Issues

Incidence of hepatic hemorrhage is rare, differs depending on etiology Mortality of hepatic rupture is high (30-75%) Patient chart review Cirrhosis/chronic liver disease, viral hepatitis, malignancy, pregnancy Coagulopathy, medications, vasculitis/connective tissue disease Recent hepatobiliary surgery, liver biopsy, or TIPS procedure

cava laceration during transcaval puncture, hepatic artery injury

Peliosis Hepatis

Rare, incidence of significant hemorrhage/rupture unknown Exact etiology unknown, variety of associations Drugs/toxins: Anabolic steroids, oral contraceptives, tamoxifen, azathioprine, 6-mercaptopurine, corticosteroids, vinyl chloride, arsenic acid Infections: Tuberculosis, HIV, Bartonella henselae Malignancies: Hematologic and nonhematologic Other: Organ transplantation, hemodialysis, celiac disease, glycogenosis type I

Other Rare Causes

Vasculitis/connective tissue diseases (e.g., polyarteritis nodosa, lupus erythematosus), hypereosinophilic syndrome, microaneurysms secondary to inflammatory processes, hepatic amyloidosis (variable data regarding risk)

CLINICAL ISSUES Epidemiology Incidence

Rare; incidence differs depending on etiology

Presentation

Sudden right upper quadrant pain radiation to shoulder, nausea, vomiting

Tachycardia, hypotension, hypovolemic shock, hemobilia (melena, jaundice, biliary pain) Important elements of chart review Cirrhosis/chronic liver disease, alcohol use, viral hepatitis, malignancy, pregnancy, coagulopathy, hypertensive disease, vasculitis/connective tissue diseases Recent hepatobiliary surgery, liver biopsy, biliary drain placement, or TIPS procedure

Macroscopic Pathology

Examine Glisson capsule for disruption; check location and status of stents and drains

Assess presence of underlying liver disease Common etiologies of hemorrhage

Tumors Pregnancy related Iatrogenic Peliosis hepatis

Microscopic Pathology

Submit representative sections of masses, hemorrhagic areas/hematomas, gross vascular lesions

Evaluate uninvolved liver with iron and trichrome reticulin stains for intrinsic disease

Very rarely, no underlying pathology identified Medications, e.g., anticoagulants, antiplatelet agents, oral contraceptives, anabolic steroids, other hormone therapy, immunosuppressive drugs

Laboratory Tests

hemoglobin/hematocrit, thrombocytopenia, prothrombin and partial thromboplastin times

Organ System Approach to Autopsy: Sudden and Unexpected Death

HEPATIC HEMORRHAGE

transaminases, alkaline phosphatase, bilirubin, and ammonia, albumin

(+) viral hepatitis serologies, -fetoprotein/other tumor markers

Prognosis

Mortality of hepatic rupture is high (30-75%) Pregnancy-related hemorrhage: Maternal mortality ~ 40%, fetal mortality ~ 30%

IMAGE FINDINGS Radiographic Findings

Ultrasound, CT scan, MR for evidence of bleeding/ rupture underlying masses, cirrhosis, other diffuse liver disease

Angiography

Diagnosis of vascular lesions (e.g., hemangiomas, pseudoaneurysms, peliosis hepatis) therapeutic interventions (e.g., embolization)

MACROSCOPIC FEATURES Sections to Be Submitted

Masses, hemorrhagic areas/hematomas, gross vascular lesions

Uninvolved liver with iron and trichrome stains for evaluation of hemosiderosis and fibrosis, reticulin stain for evaluation of sinusoidal architecture

External Examination

Pallor of skin, mucous membranes, conjunctiva

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Organ System Approach to Autopsy: Sudden and Unexpected Death

HEPATIC HEMORRHAGE Jaundice/scleral icterus, periumbilical caput medusae, skin spider angiomas Evidence of recent surgical procedures, drains

Internal Examination

Hemoperitoneum, hemothorax, ascites, hepatosplenomegaly

Disruption of Glisson capsule, location and status of stents and drains

Organ Examination

Location of hemorrhage/hematoma: Intraparenchymal, subcapsular rupture, gallbladder bed, in bile ducts/gallbladder Underlying liver disease, cirrhosis/nodularity, gross thrombi in large vessels Tumors Hepatocellular carcinoma Single, multiple or diffusely nodular, color variable, capsule, tumor thrombi in veins/ inferior vena cava; usually in background of cirrhosis Hepatocellular adenoma Single, rarely multiple, color variable, well circumscribed, usually not encapsulated, noncirrhotic background Hemangioma Usually single, subcapsular, well circumscribed, nonencapsulated, spongy, soft, red-purple, blood filled thrombosis, fibrosis, and calcification Metastatic neoplasms Usually multiple, variable in size, location, and gross appearance; noncirrhotic background Pregnancy related Subcapsular hematoma rupture, right lobe > left lobe Patchy necrosis Peliosis hepatis Multiple blood-filled cystic spaces ranging from few mm to few cm in diameter, randomly distributed, necrosis Amyloidosis Pale, friable parenchyma, capsular tears

MICROSCOPIC PATHOLOGY Histologic Features

Normal-appearing hepatocytes present in cords/ sheets 1-3 cells thick with normal reticulin framework Absence of normal portal tracts within tumor, scattered isolated arteries/veins, no cytologic atypia, nucleoli, mitoses, or vascular invasion Portal tract-like structures with inflammation, ductular reaction and vessels, but no bile ducts (inflammatory type) Hemangioma Usually cavernous type Vascular spaces lined by single layer of bland, flattened endothelial cells fibrosis, thrombosis, calcification Preeclampsia/eclampsia HELLP syndrome Periportal hemorrhage, fibrin deposition, and hepatocellular necrosis Fibrin thrombi in portal vessels, infarction, nonspecific portal inflammation Peliosis hepatis Parenchymal pattern: Irregular blood-filled spaces/blood lakes without endothelial lining hepatocellular necrosis Phlebectatic pattern: Rounded centrilobular bloodfilled spaces lined by endothelial cells or fibrous tissue, compresses adjacent parenchyma without significant necrosis, perisinusoidal fibrosis B. henselae infection (bacillary peliosis hepatis): Gram-negative bacilli, (+) Warthin-Starry stain, bacteria in clumps within smudge-like, granular material in a myxoid stroma, dilated vascular spaces Amyloidosis Deposition of hyaline material that is Congo red positive, usually in periportal space of Disse or sometimes central; may obstruct sinusoids or involve portal vessels, loss of normal reticulin framework Very rarely, no underlying pathology is identified

REPORTING CRITERIA Key Elements to Report

Location and type of hemorrhage Etiology and risk factors for hemorrhage Presence of underlying liver disease Effect of hemorrhage and underlying disease on other organs

Hepatocellular carcinoma

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Many histologic patterns, all show abnormal or loss of reticulin framework Endothelial cells/sinusoidal vessels surrounding tumor cells, i.e., "capillarization of sinusoids" ([+] immunostain for CD34) Cells are polygonal with abundant eosinophilic or less often clear cytoplasm, high N:C ratio, nuclei with coarse chromatin nucleoli, steatosis, Mallory-Denk bodies, or bile production Vascular invasion and mitotic figures common Hepatocellular adenoma

SELECTED REFERENCES 1. 2.

Vigil-De Gracia P et al: Pre-eclampsia/eclampsia and hepatic rupture. Int J Gynaecol Obstet. 118(3):186-9, 2012 Zhu Q et al: Predictors and clinical outcomes for spontaneous rupture of hepatocellular carcinoma. World J Gastroenterol. 18(48):7302-7, 2012 Jr MA et al: Spontaneous rupture of hepatic hemangiomas: A review of the literature. World J Hepatol. 2(12):428-33, 2010 Ripamonti R et al: Transjugular intrahepatic portosystemic shunt-related complications and practical solutions. Semin Intervent Radiol. 23(2):165-76, 2006

Gross and Microscopic Features (Left) This hepatic hematoma occurred after percutaneous biliary drain placement, which resulted in portal vein injury and arterial-portal venous fistula formation (confirmed on premortem hepatic angiogram). (Right) Section through the hematoma shows adjacent hepatic parenchyma with patchy coagulative necrosis .

(Left) Hemoperitoneum occurred after percutaneous liver biopsy in a patient on anticoagulant therapy. Note the liver and gallbladder . (Right) The inflammatory (a.k.a. telangiectatic) type of hepatocellular adenoma is characterized by portal tractlike structures containing inflammatory infiltrates and marked sinusoidal dilatation .

Organ System Approach to Autopsy: Sudden and Unexpected Death

HEPATIC HEMORRHAGE

(Left) A microscopic focus of the parenchymal pattern of peliosis hepatis in a patient with a history of anabolic steroid use shows sinusoidal dilatation and an irregular blood-filled space with associated hepatocellular necrosis . (Right) A cavernous hemangioma is composed of blood-filled spaces lined by bland, flattened endothelial cells .

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Organ System Approach to Autopsy: Sudden and Unexpected Death

HEMORRHAGIC PANCREATITIS

Hemorrhagic necrosis of the head and body of the pancreas developed following distal pancreatectomy/ splenectomy for tumor.

TERMINOLOGY Definitions

Acute hemorrhagic pancreatitis: Necrotizing pancreatitis with disruption of microvasculature, leading to severe systemic complications Grey Turner sign: Bruising of flanks due to retroperitoneal hemorrhage Cullen sign: Periumbilical bruising due to subcutaneous hemorrhage

ETIOLOGY/PATHOGENESIS

Necrosis, organ failure, sepsis, pancreatic/ peripancreatic collections, status post surgery for debridement

CLINICAL ISSUES Epidemiology Incidence

Occurs in 20-30% of all patients with acute pancreatitis Fatal hemorrhagic complications ~ 2-15%

Presentation

Choledocholithiasis and alcohol-related: Most

Symptoms: Epigastric pain radiation to back,

common Metabolic (hyperlipidemia, hypercalcemia) Infections (viral, bacterial, parasitic) Medications/toxins (antiretroviral drugs, valproic acid, diuretics, scorpion venom) Postoperative (pancreaticobiliary or other abdominal surgery), post endoscopic retrograde cholangiopancreatography (ERCP) Anatomic abnormalities/obstruction (pancreas divisum, tumors) Ischemia related (shock, vasculitis, thromboemboli) Trauma

Signs: Fever, hypovolemic shock, disseminated

Necrosis and enzyme leakage causing pseudoaneurysm

Risk Factors for Hemorrhage

Etiologies of Acute Pancreatitis

Pathogenesis of Hemorrhage in Pancreatitis

There is also peritonitis with dullness and green-brownblack discoloration of the serosal and peritoneal surfaces in the same patient.

formation or vascular rupture with bleeding into peritoneal cavity, retroperitoneal space, and other organs Bleeding into pancreatic/peripancreatic collections (abscesses, pseudocysts) with rupture erosion of adjacent vessels Splenic vein thrombosis resulting in left-sided portal hypertension and bleeding from upper GI varices

nausea, vomiting, anorexia

intravascular coagulation (DIC), respiratory distress, sepsis, hematemesis, melena, Grey Turner or Cullen sign, peritoneal signs

Laboratory Tests

serum amylase and lipase, hemoglobin and hematocrit

Leukocytosis, hyperglycemia, hypocalcemia Multiorgan failure ( BUN and creatinine, abnormal LFTs, arterial pO)

Prognosis

Overall mortality due to hemorrhage ~ 20-50% Usually diagnosed premortem, but can occasionally result in sudden death due to multiorgan failure

IMAGE FINDINGS CT Findings

Enlarged pancreas, edema, necrotic areas, hematomas, abscesses, pseudocysts

Key Facts Terminology

Acute hemorrhagic pancreatitis: Necrotizing pancreatitis with disruption of microvasculature, leading to severe systemic complications

Etiology

Choledocholithiasis and alcohol related are most

Hemoperitoneum, ascites, peritonitis Pancreatic/peripancreatic abscesses or pseudocysts Indurated, edematous, red-black hemorrhagic parenchyma necrosis

Peripancreatic/mesenteric fat necrosis Peripancreatic vascular lesions (thromboses, ruptures, pseudoaneurysms)

common Metabolic disorders, infections, medications/toxins, obstruction, postoperative, ischemia, trauma

Gastric/esophageal varices, stress ulcers, perforations,

Clinical Issues

Interstitial edema and hemorrhage Acute inflammation necrosis involving acini, ducts,

Incidence of fatal hemorrhagic complications ~ 2-15%

Overall mortality due to hemorrhage ~ 20-50%

Macroscopic Pathology

fistulas, strictures

Microscopic Pathology and islets of Langerhans

Other organs: Diffuse alveolar damage, bronchopneumonia, acute tubular injury/necrosis, hepatic centrilobular congestion/necrosis

Signs of sepsis, Grey Turner or Cullen sign

Angiography

Liver: Congestion and patchy necrosis (shock), portal

Diagnostic (thrombosed vessels, pseudoaneurysms,

vein thrombosis

active bleeding) and therapeutic (embolization)

MICROSCOPIC PATHOLOGY MACROSCOPIC FEATURES External Examination

Skin: Grey Turner or Cullen sign, jaundice, surgical incisions/drains, erythematous nodules (usually pretibial due to subcutaneous fat necrosis) Signs of sepsis: Petechiae, peripheral edema/anasarca

Internal Examination

Hemoperitoneum, ascites, peritonitis (dull surfaces green/yellow fibrinopurulent exudate)

Surgical anastomoses, vascular therapeutic interventions

Pleural or pericardial effusions

Organ Examination Pancreas

Indurated, edematous, red-black hemorrhagic parenchyma necrosis Peripancreatic/mesenteric fat necrosis: Yellow-white chalky nodules in adipose tissue Peripancreatic vascular lesions (thromboses, ruptures, pseudoaneurysms) Pseudocyst: Usually unilocular with thick fibrous wall, smooth or roughened inner lining with adherent debris and cloudy, brown, or hemorrhagic fluid contents, usually not connected to pancreatic ductal system Abscess: Purulent debris/pus within a fibrous tissue wall around or within pancreas Fistulas from pancreas to other organs Gastrointestinal tract Gastric/esophageal varices, gastric stress ulcers Perforations, fistulas, strictures Lungs: Edema/congestion, consolidation, abscesses Kidneys: Cortical pallor and medullary congestion (acute tubular injury/necrosis)

Histologic Features

Organ System Approach to Autopsy: Sudden and Unexpected Death

HEMORRHAGIC PANCREATITIS

Pancreas

Interstitial edema and hemorrhage Acute inflammation necrosis involving acini, ducts, and islets of Langerhans Vascular injury with necrosis of vessel wall Fat necrosis calcification Pseudocysts: Fibrous wall with granulation tissue, calcifications, cholesterol clefts, inflammation, and giant cells without epithelial lining, filled with necrotic/hemorrhagic debris Other organs: Diffuse alveolar damage, bronchopneumonia, acute tubular injury/necrosis, hepatic centrilobular congestion/necrosis

REPORTING CRITERIA Key Elements to Report

Risk factors for developing pancreatitis, risk factors for hemorrhagic complications, effects on other organs

SELECTED REFERENCES 1.

Banks PA et al: Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 62(1):102-11, 2013 Sharma PK et al: Hemorrhage in acute pancreatitis: should gastrointestinal bleeding be considered an organ failure? Pancreas. 36(2):141-5, 2008 Fu CY et al: Timing of mortality in severe acute pancreatitis: experience from 643 patients. World J Gastroenterol. 13(13):1966-9, 2007 Flati G et al: Potentially fatal bleeding in acute pancreatitis: pathophysiology, prevention, and treatment. Pancreas. 26(1):8-14, 2003

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Organ System Approach to Autopsy: Sudden and Unexpected Death

HEMORRHAGIC PANCREATITIS

Pancreatic and Peripancreatic Findings (Left) This case of acute pancreatitis with peripancreatic hemorrhage/ hematoma developed status post ERCP. (Right) Histologic section from the same patient shows intraparenchymal and peripancreatic hemorrhage/ hematoma and a residual islet .

(Left) Neutrophils are infiltrating the pancreatic parenchyma in this case of acute pancreatitis. (Right) Peripancreatic fat necrosis is composed of "ghosts" of adipocytes with bluegray to pink cytoplasm and loss of nuclei . Adjacent hemorrhage is also present.

(Left) This bivalved peripancreatic pseudocyst has a thin, partially calcified and necrotic fibrous wall hemorrhagic cyst contents . (Right) Histologic sections of the peripancreatic pseudocyst show a fibrous wall containing scattered calcifications . No epithelial lining is present. Hemorrhagic, fibrinous, and necrotic debris is present within the pseudocyst .

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Other Organ Changes (Left) Gastric stress ulcers with a round, punched-out appearance and smooth, flat, nonindurated borders can occur in patients with hemorrhagic pancreatitis. (Right) A section through a gastric stress ulcer shows mucosal erosion and hemorrhage . The adjacent mucosa is normal and partially autolyzed.

(Left) A left-sided pleural effusion composed of clear, yellow serous fluid occurred in a patient with hemorrhagic pancreatitis. (Right) Diffuse alveolar damage, as seen in acute respiratory distress syndrome, with alveolar hyaline membranes , fibrin deposition, and acute inflammation in alveolar spaces can be a complication of pancreatitis.

Organ System Approach to Autopsy: Sudden and Unexpected Death

HEMORRHAGIC PANCREATITIS

(Left) This section from the kidney shows acute tubular injury with dilated tubules, epithelial necrosis and sloughing , and pigmented tubular casts . (Right) Centrilobular/ perivenular congestion and hepatocellular necrosis are due to shock resulting from hemorrhagic pancreatitis. Note the central vein .

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE LIVER FAILURE

Liver with innumerable tan-yellow metastatic deposits and associated parenchymal necrosis is from a patient with breast cancer who presented with acute liver failure.

TERMINOLOGY Abbreviations

Acute liver failure (ALF)

Definitions

Coagulopathy (international normalized ratio [INR] 1.5) and encephalopathy (any degree of mental alteration) resulting from severe liver injury for < 26 weeks duration without preexisting liver disease/ cirrhosis

Histologic section of the liver shows metastatic breast carcinoma infiltrating through the sinusoidal spaces.

Contraceptive steroids, pregnancy, myeloproliferative disorders, thrombophilia, hepatocellular carcinoma

Autoimmune Hepatitis

Usually causes chronic hepatitis but occasionally presents with ALF

Metabolic Disorders

Wilson disease: Uncommon; usually seen in young patients

Acute fatty liver of pregnancy: 3rd trimester, enzyme deficiency defects in fatty acid oxidation

ETIOLOGY/PATHOGENESIS

Metabolic disorders and neonatal hemochromatosis in

Drug/Toxin Induced

Malignant Infiltration of Liver

Acetaminophen: Leading cause of liver failure in USA, dose-related toxicity Idiosyncratic drug reaction: Antibiotics, nonsteroidals, anticonvulsants, statins, herbals, supplements Mushroom poisoning: Toxin produced by fungal cells of toxic mushrooms, usually Amanita phalloides

Viral Hepatitis

Leading cause of ALF worldwide Common: Hepatitis A, E, B (either new infection or reactivation), or D (coinfection with hepatitis B vs. superinfection) Uncommon: Herpes simplex virus (HSV), EpsteinBarr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), or varicella-zoster virus (VZV), in setting of immunosuppression

Ischemic/Hemodynamic

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children < 1 year old are rare

Lymphomas, melanoma, breast carcinoma, and small cell carcinoma are most likely to cause ALF

Indeterminate ~ 15% of cases

CLINICAL ISSUES Epidemiology Incidence

Rare; ~ 2,000 cases/year in USA, usually young patients ~ 5-10% of liver transplants annually

Presentation

Jaundice, fatigue, fever, right upper quadrant pain, altered mental status, seizures

Shock liver after cardiac arrest, hypovolemia/

No history or signs of chronic liver failure/cirrhosis

hypotension, severe congestive heart failure, heat stroke Drug related (cocaine, methamphetamine) Budd-Chiari syndrome: Acute hepatic vein or inferior vena cava thrombosis venous outflow obstruction

Laboratory Tests

prothrombin and partial thromboplastin times, INR 1.5; transaminases, bilirubin, ammonia

Hypoglycemia, hyponatremia, lactic acidosis

Key Facts Terminology

ALF: Coagulopathy (INR 1.5) and encephalopathy (any degree of mental alteration) resulting from liver injury for < 26 weeks duration without preexisting liver disease/cirrhosis

Etiology

Clinical Issues

~ 2,000 cases/year in USA, usually young patients, mortality ~ 30%

Common immediate causes of death: Cerebral edema/herniation, multiorgan failure, infection/ sepsis

Drug-/toxin-induced viral hepatitis: Most common Ischemic/hemodynamic causes (shock liver, severe

Macroscopic Pathology

congestive heart failure, heat stroke, drug related, Budd-Chiari syndrome) Autoimmune hepatitis Metabolic disorders (Wilson disease, acute fatty liver of pregnancy) Malignancy Indeterminate etiology (~ 15% of cases)

Microscopic Pathology

Thrombocytopenia, fibrin degradation products, fibrinogen (in disseminated intravascular coagulation [DIC]) IgG and (+) autoantibodies (autoimmune hepatitis) Hemolytic anemia, serum ceruloplasmin, urine and hepatic copper levels (Wilson disease) Viral antibodies/antigens (+) acetaminophen levels (depending on time of ingestion), other drug levels

Prognosis

Mortality ~ 30%, differs depending on etiology Common immediate causes of death

Cerebral edema/intracranial hypertension herniation, multiorgan failure, infection/sepsis

IMAGE FINDINGS Radiographic Findings

Hepatic atrophy or hepatomegaly heterogeneous, hypoattenuated foci (necrosis)

Surface nodularity due to alternating necrosis and regeneration (may mimic cirrhosis) Evidence of portal hypertension (also present in cirrhosis), i.e., splenomegaly, ascites, collateral vessel formation, hepatofugal (reverse) flow in portal vein

MACROSCOPIC FEATURES External Examination

Jaundice/scleral icterus Petechiae/purpura, gangrene (sepsis, DIC) Mucocutaneous hemorrhage, bleeding from surgical/ procedural sites (DIC)

Internal Examination Ascites, splenomegaly

Organ Examination Liver

Atrophic or enlarged

Wrinkled capsule, nodular surface, necrosis Findings may differ depending on cause of ALF Varying degrees of necrosis, parenchymal collapse, ductular reaction, regeneration

Top Differential Diagnoses Cirrhosis/chronic liver failure

Wrinkled capsule, nodular surface Soft cut surface, necrotic areas, regenerative nodules, congestion, green discoloration (cholestasis) Yellow fatty liver (acute fatty liver of pregnancy, drug reaction) Thrombi in hepatic veins/inferior vena cava (BuddChiari syndrome) GI tract: Ulcers, ischemic enterocolitis, rarely hemorrhagic/necrotizing pancreatitis Kidneys: Cortical pallor, medullary congestion Lungs: Edema/congestion, consolidation, abscesses Brain: Flattened gyri, narrowed sulci and ventricular compression (cerebral edema), herniation (subfalcine, transtentorial/uncinate, tonsillar), hemorrhagic foci in midbrain and pons with transtentorial herniation Heart: Subendocardial/myocardial mottling yellowtan areas with hyperemic borders (infarction)

Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE LIVER FAILURE

MICROSCOPIC PATHOLOGY Histologic Features Hepatic findings

May differ depending on cause of ALF Varying degrees of necrosis (zonal, confluent, multiacinar, bridging, panacinar), parenchymal collapse, ductular reaction, regeneration Canalicular ductular cholestasis (sepsis) Other organs Lungs: Aspiration pneumonitis, bronchopneumonia, abscesses, diffuse alveolar damage GI tract: Mucosal ulcers, ischemic enterocolitis, acute pancreatitis Kidneys: Acute tubular injury/necrosis Heart: Subendocardial/myocardial contraction band/coagulative necrosis, edema, hemorrhage, inflammation (infarction) Brain: Hemorrhage in areas of herniation DIC: Widespread microthrombi ischemic necrosis of various organs/tissues, schistocytes on peripheral blood smear

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE LIVER FAILURE

Histologic Features of Acute Liver Failure Etiologies Etiology

Necrosis

Inflammation Steatosis

Cholestasis Bile Duct Other Findings Injury

Acetaminophen + coagulative, toxicity perivenular midzonal

+ in remaining hepatocytes

Idiosyncratic drug reaction

Mushroom poisoning

+ perivenular

Hepatitis A

+ periportal

+ perivenular

plasma cells

+ active chronic hepatitis

Ground-glass hepatocytes, "sanded" nuclei (pale pink inclusions)

Hepatitis B D +

Varies depending on drug

Hepatitis E

HSV

+ irregular/ geographic coagulative

Intranuclear inclusions, chromatin margination, multinucleation

EBV

+ (rare)

+ diffuse sinusoidal lymphocytic infiltrate

CMV

+ (rare)

+ neutrophilic microabscesses

Intranuclear & intracytoplasmic inclusions

Acute ischemic injury

+ coagulative, perivenular midzonal

- or scant

+ in remaining hepatocytes

congestion

Budd-Chiari syndrome

Severe congestion, sinusoidal dilatation, preserved portal tracts, portal vein thrombi

Autoimmune hepatitis

+ perivenular, confluent bridging

+ lymphoplasmacytic interface

Hepatocyte rosettes

Wilson disease

+ chronic or active

Mallory-Denk bodies

+ lobular

+ microvesicular

Acute fatty liver of pregnancy

HSV = herpes simplex virus; EBV = Epstein-Barr virus; CMV = cytomegalovirus

ANCILLARY TESTS Immunohistochemistry

Immunostains for hepatitis B surface/core antigens, HSV, CMV, VZV, HHV6

In Situ Hybridization EBER for EBV

Special Stains

Hepatocellular copper/copper-binding protein stains (+) in Wilson disease May be patchy or absent, not specific for Wilson disease, may be present in chronic cholestasis

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atrophy or hepatomegaly, evidence of portal hypertension Macroscopic: Diffusely (micro- or macro-) nodular parenchyma composed of regenerative nodules separated by fibrous bands, ascites, splenomegaly Microscopic: Disruption of normal architecture by scarring/bridging fibrosis surrounding nodules of hepatocytes without central veins

DIAGNOSTIC CHECKLIST Final Report Should Include

Etiology and whether it was cause of death or contributing factor

DIFFERENTIAL DIAGNOSIS

ALF risk factors, effects on other organs

Cirrhosis/Chronic Liver Failure

SELECTED REFERENCES

Similar clinical presentation but 26 weeks duration

Radiographic: Surface/parenchymal nodularity,

and history/signs of underlying chronic liver disease Some similar etiologies (hepatitis B D, autoimmune hepatitis, Wilson disease, drug-induced hepatitis)

1. 2.

Bernal W et al: Acute liver failure. N Engl J Med. 369(26):2525-34, 2013 Das P et al: A retrospective autopsy study of histopathologic spectrum and etiologic trend of fulminant hepatic failure from north India. Diagn Pathol. 2:27, 2007

Microscopic and Gross Features (Left) Bridging necrosis extends from one central vein to another in this case of autoimmune hepatitis. Clusters of plasma are present in the cells inflammatory infiltrate. (Right) Acute imatinib (Gleevec)-induced liver injury is characterized by diffuse, predominantly lymphocytic lobular inflammation, scattered acidophil bodies , and canalicular and hepatocellular cholestasis .

(Left) This liver is from an immunosuppressed patient presented with acute liver failure due to herpes simplex virus (HSV) infection. The liver parenchyma is extensively necrotic. The nuclei in scattered residual hepatocytes show glassy intranuclear inclusions with chromatin margination . (Right) Immunostain for HSV1/2 of the same case highlights numerous infected hepatocytes. Note nuclear staining .

Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE LIVER FAILURE

(Left) Large irregular areas of hepatic parenchymal necrosis are the result of ischemia due to hypovolemic shock. (Courtesy D. Rubin, MD.) (Right) The hepatic parenchyma in this case of hypovolemic shock shows submassive necrosis involving centrilobular/ perivenular and midzonal . Viable periportal regions hepatocytes show fatty change .

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Organ System Approach to Autopsy: Sudden and Unexpected Death

PREGNANCY COMPLICATIONS

H&E stain of the lung in a case of a postpartum maternal death shows amorphous material within a vascular space consistent with an amniotic fluid embolism.

TERMINOLOGY Definitions

Maternal mortality (WHO)

Death of a woman while pregnant or within 42 days of termination of pregnancy (delivery) Irrespective of gestational duration or site (e.g., ectopic) Any cause related to or aggravated by pregnancy or its management Not from accidental or incidental causes Late maternal mortality From 42 days to 1 year after termination

H&E photomicrograph from an autopsy lung in an amniotic fluid embolism death shows fetal "squames" or sloughed amniotic lining cells lodged in distal (subpleural) pulmonary arterioles.

Coincidental maternal death

Result from diseases or injuries not related to pregnancy Examples Homicide Accidents Risk factors associated with maternal death Inadequate maternal care Substance abuse Medical comorbidities Previous pregnancy problems Hypertensive disorders of pregnancy

CLINICAL SUMMARY EPIDEMIOLOGY Incidence

Maternal mortality rate

Developed nations: < 10/100,000 live births Developing nations: 100-1,000/100,000 live births

Presentation

Direct obstetric death

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Result from obstetric complications (pregnancy, labor, and puerperium) Examples Amniotic fluid embolism Uterine rupture Peripartum cardiomyopathy Indirect obstetric death Result from preexisting disease or disease that developed during pregnancy Not directly due to obstetric cause, but aggravated by pregnancy Examples Congenital heart defect Idiopathic pulmonary hypertension Aortic dissection in Marfan syndrome

Clinical Information

Current pregnancy history Gravida/para status Mode of delivery

Delivery procedures (cesarean section, vacuum assisted, forceps) APGAR scores Infection serologies TORCH, group B Streptococcus

Past Medical History

Heart or lung disease, anemia, hypertension, thrombophilia/coagulopathy

Medications

MACROSCOPIC FINDINGS Autopsy, Mother

Per normal routine Extensive sampling of lungs Photograph liberally Consider fixing pelvic organs en bloc and examining with obstetrician present

Autopsy, Fetus

Per normal routine Cultures (blood, CSF)

Surgical Specimens

Obtain placenta, hysterectomy, or other organs removed in proximity to death After surgical report is finalized

MICROSCOPIC FINDINGS Amniotic Fluid Embolism

Amniotic fluid, fetal cells, lanugo hair, and other debris enter maternal blood stream causing cardiorespiratory collapse and disseminated intravascular coagulation (DIC) Can occur during active labor, delivery, or post delivery Mortality rate: 11-44% Risk factors include Maternal age 35 years Cesarean section Placenta previa Multiparity Pathophysiology poorly understood as fetal cells often found in asymptomatic women Immunologic mechanisms, amniotic fluiddependent anaphylactic reaction, and complement activation have been proposed as potential pathophysiologic mechanisms Amniotic "squames" within pulmonary arterioles and capillaries, parauterine vessels Cytokeratin staining used to highlight Other supplemental stains may be used PAS or Alcian blue to visualize mucus Sudan III to show fatty substances

Postpartum Hemorrhage

Uterine atony Uterine rupture or genital tract trauma

Risk factors include prior cesarean section, connective tissue disorders, instrumentation Retained placenta

Prepartum Hemorrhage Ectopic pregnancy

Those occurring in intramural portion of tube (cornual ectopic) and cesarean section scar are covered by myometrium and grow to larger size than typical tubal ectopic before symptomatic Rupture later than tubal ectopic More likely to cause catastrophic bleeding and death Unskilled abortion Placenta previa Placental abruption

Placenta Accreta

Placental invasion of myometrium

Villi in direct contact with superficial myometrial smooth muscle (no intervening decidua)

Associated with previous uterine surgical scar sites, especially cesarean section scars Risk increases with number of prior cesarean sections Most associated with placenta previa Increta Invasion deep into myometrium Percreta Invasion through myometrium into peritoneal space Invasion into other organs, typically bladder Maternal death: 4-7% Hemorrhage with cardiovascular collapse Average blood loss 3,000-5,000 mL but can be much higher Secondary causes of death include DIC, renal failure, acute respiratory distress

Puerperal Sepsis

Genital tract nidus of infection

Occurring between rupture of membranes or labor and postpartum day 42 2 or more of following present Pelvic pain Fever Abnormal vaginal discharge Abnormal smell of discharge Delay in reduction of size of uterus Possible sources Chorioamnionitis Laceration with necrotizing fasciitis Nosocomial infection

Organ System Approach to Autopsy: Sudden and Unexpected Death

PREGNANCY COMPLICATIONS

Preeclampsia/Eclampsia

Hypertension (> 140/> 90), proteinuria, hyperreflexia Maternal complications

Seizures Stroke Renal failure Glomerular endotheliosis at autopsy Liver failure Hepatic necrosis in periportal zone 1 Adult respiratory distress syndrome, severe pulmonary edema Cardiopulmonary arrest Fetal complications Intrauterine growth restriction Stillbirth Complications associated with prematurity Placental changes Decidual vasculopathy Atherosis Ischemic changes/pressure-related injury Infarcts: Large, central, and of variable age Hypermaturity of villi HELLP syndrome develops in 10-20% of preeclampsia cases H = hemolysis ( breakdown of red blood cells) EL = elevated liver enzymes LP = low platelet count Overall maternal mortality: 3.5% Approaches 50% in cases of liver rupture

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Organ System Approach to Autopsy: Sudden and Unexpected Death

PREGNANCY COMPLICATIONS Pregnancy-Associated Hematologic Disorders Thrombophilia

Combined with extrinsic compression of iliac veins and vena cava increases risk of thromboembolism Microangiopathic thrombocytopenia in preeclampsia/ eclampsia and HELLP syndrome Thrombocytopenic purpura (TTP) Atypical hemolytic uremic syndrome

Spontaneous Coronary Dissection

Constitutional or acquired arterial wall weakness

10.

added to mechanical stress

Peripartum Cardiomyopathy

Dilated cardiomyopathy that develops between last

11.

month of pregnancy and 1st 5 months after delivery

Relationship between pregnancy and dilated

cardiomyopathy is unclear but may involve hormonal, inflammatory, familial, or hemodynamic factors Death may occur form progressive heart failure, arrhythmia, or thromboembolism USA death rate: 3.3-9.6%

ANCILLARY STUDIES

12.

13.

14.

15.

Postmortem Samples

Blood cultures (aerobic and anaerobic) Genital tract, perineum cultures Toxicology

16.

Antemortem Samples

Retrieve and store Remain aware of sample stability issues

17.

DIAGNOSTIC CHECKLIST

18.

Clinically Relevant Pathologic Features

In event of unexplained maternal death, autopsy must be performed

Carefully sample lungs to look for amniotic fluid embolism Leading cause of unexplained death

SELECTED REFERENCES 1. 2.

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Jariwala MC Sr: [51-OR.] Pregnancy Hypertens. 5(1):26, 2015 Mehrabadi A et al: Contribution of placenta accreta to the incidence of postpartum hemorrhage and severe postpartum hemorrhage. Obstet Gynecol. 125(4):814-21, 2015 Nair M et al: Factors associated with maternal death from direct pregnancy complications: a UK national case-control study. BJOG. 122(5):653-62, 2015 Woo YS et al: Ischemic stroke related to an amniotic fluid embolism during labor. J Clin Neurosci. 22(4):767-768, 2015 Clark SL: Amniotic fluid embolism. Obstet Gynecol. 123(2 Pt 1):337-48, 2014

Fitzpatrick KE et al: The management and outcomes of placenta accreta, increta, and percreta in the UK: a population-based descriptive study. BJOG. 121(1):62-70; discussion 70-1, 2014 Ito F et al: Incidence, diagnosis and pathophysiology of amniotic fluid embolism. J Obstet Gynaecol. 34(7):580-4, 2014 Yoneyama K et al: Clinical characteristics of amniotic fluid embolism: an experience of 29 years. J Obstet Gynaecol Res. 40(7):1862-70, 2014 Zosmer N et al: The morbidly adherent placenta: early accurate diagnosis is essential for the meaningful interpretation of outcomes. BJOG. 121(10):1314-5, 2014 Abildgaard U et al: Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review. Eur J Obstet Gynecol Reprod Biol. 166(2):117-23, 2013 Guillaume A et al: Amniotic fluid embolism: 10-year retrospective study in a level III maternity hospital. Eur J Obstet Gynecol Reprod Biol. 169(2):189-92, 2013 Hikiji W et al: Fatal amniotic fluid embolism with typical pathohistological, histochemical and clinical features. Forensic Sci Int. 226(1-3):e16-9, 2013 Saucedo M et al: Ten years of confidential inquiries into maternal deaths in France, 1998-2007. Obstet Gynecol. 122(4):752-60, 2013 Kanayama N et al: Maternal death analysis from the Japanese autopsy registry for recent 16 years: significance of amniotic fluid embolism. J Obstet Gynaecol Res. 37(1):58-63, 2011 Sinicina I et al: Forensic aspects of post-mortem histological detection of amniotic fluid embolism. Int J Legal Med. 124(1):55-62, 2010 Sliwa K et al: Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. Eur J Heart Fail. 12(8):767-78, 2010 Turillazzi E et al: Amniotic fluid embolism: still a diagnostic enigma for obstetrician and pathologist? Acta Obstet Gynecol Scand. 88(7):839-41, 2009 Silver RM et al: Maternal morbidity associated with multiple repeat cesarean deliveries. Obstet Gynecol. 107(6):1226-32, 2006

Microscopic and Gross Features (Left) The presence of fetal "squames" within the pulmonary arterial circulation is pathognomonic for amniotic fluid embolism in a postpartum death. This is often associated with disseminated intravascular coagulation systemically. (Right) Mucicarmine staining can be used to help highlight fetal "squames" in the pulmonary arterial branches. They stain positive for mucin (pink) due to their rich mucopolysaccharide content.

(Left) Gross image of a term uterus shows a large amniotic fluid embolism located within a dilated vessel of the lower uterine segment. (Right) Section of myocardium shows 2 moderately dilated vascular spaces that contain amorphous material consistent with amniotic fluid emboli.

(Left) Blood vessel from bone marrow taken at autopsy shows a small eosinophilic thrombus . Thrombi within the microvasculature are responsible for RBC fragmentation and thrombocytopenia in TTP as a complication of pregnancy. (From DP: Blood & Bone Marrow.) (Right) Intravascular thrombi are highlighted by immunoperoxidase staining for CD31 in this case of fatal TTP. Note the compromise of vascular lumina. (From DP: Blood & Bone Marrow.)

Organ System Approach to Autopsy: Sudden and Unexpected Death

PREGNANCY COMPLICATIONS

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Organ System Approach to Autopsy: Sudden and Unexpected Death

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PREGNANCY COMPLICATIONS

Gross and Microscopic Features (Left) Gross photograph of the uterus in a case of placenta percreta shows the umbilical cord going through the fundal hysterotomy . There is a frank breech of the anterior uterine wall with the placenta appearing as a fungating mass . (Right) Transverse section through the lower uterine segment in another case shows placental invasion into the myometrium and through the serosal surface . Invasion into surrounding structures, typically bladder, can result in massive hemorrhage and death.

(Left) A section taken from the lower uterine segment shows placenta percreta with absent decidua, absent myometrium, and omental adipose tissue adherent to the uterine serosa. (From DP: Placenta.) (Right) In this section taken from an area of placenta percreta, fibrinoid at the base of the placenta is adjacent to omental adipose tissue and bundles of smooth muscle from the bladder. (From DP: Placenta.)

(Left) This small placenta has multiple infarcts of variable age, including infarction hematomas, as most commonly seen in preterm preeclampsia. White infarcts are 7 days old, whereas red infarcts are more recent (2-3 days). (From DP: Placenta.) (Right) This section from the free membranes in a case of preeclampsia shows an acute atheroma within a maternal vessel of the decidua parietalis. There is fibrinoid necrosis , foamy macrophages , and a cuff of surrounding lymphocytes . (From DP: Placenta.)

Radiologic, Microscopic, and Gross Features (Left) CT scan of the liver shows a woman with severe preeclampsia and HELLP syndrome. There are intrahepatic hemorrhages and a hemoperitoneum . Maternal death approaches 50% in cases of liver rupture. (From DI: Abdomen.) (Right) H&E stain highlights large thrombi with entrapped red blood cells and red cell fragments in the hilar arterioles of 2 adjacent glomeruli from a pregnant woman with HELLP syndrome. (From DP: Kidney.)

(Left) Intraoperative photo of a cornual ectopic shows an obvious bulge and thinning of the overlying myometrium . These often rupture later in pregnancy than a tubal ectopic and are, therefore, more likely to cause catastrophic bleeding and death. (From DI: Obstetrics.) (Right) Gross pathology shows a ruptured uterus secondary to a cesarean section ectopic pregnancy. A 13-week fetus is still attached to the hemorrhagic placenta . The cervix is detached. (From DI: Obstetrics.)

(Left) CT scan in a patient with acute uterine rupture shows the open anterior margins of the uterus . The fetal head is within the maternal peritoneal cavity and is surrounded by a large hemoperitoneum , which is making the borders of the uterus difficult to see. (Right) Radiograph of the abdomen in the same patient shows the the fetal head high in the maternal abdomen. It is being displaced out the pelvis by the massive hemorrhage.

Organ System Approach to Autopsy: Sudden and Unexpected Death

PREGNANCY COMPLICATIONS

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE

In this case of anti-GBM crescentic glomerulonephritis, the glomerulus shows marked parietal epithelial cell proliferation (crescent) with associated inflammatory cells and fibrinoid necrosis .

TERMINOLOGY

Rhabdomyolysis Post surgery

Abbreviations

Urinary Obstruction

Acute renal failure (ARF)

Synonyms

Acute kidney injury (AKI)

Definitions

Sudden sustained decline of glomerular filtration rate (GFR) associated with uremia, fall in urine output, and serum creatinine (SCr) increase of 0.5 mg/dL in patients with baseline SCr 1.9 mg/ dL 1 mg/dL in patients with baseline SCr between 2 and 4.9 mg/dL 1.5 mg/dL in patients with baseline SCr 5 mg/ dL

ETIOLOGY/PATHOGENESIS Glomerular Diseases

Drug/Toxin Induced

Hypersensitivity reaction: Antibiotics, nonsteroidals, protein supplements, proton pump inhibitors

Cocaine

Systemic Disorders

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In anti-glomerular basement membrane-mediated glomerulonephritis, there is bright linear glomerular basement staining for IgG . In Bowman space, a crescent can be identified .

Hypotension Hypertension Hypovolemia Sepsis

Nephrolithiasis Malignancies in urinary tract and prostate

Vascular

Renal vein thrombosis Renal artery thrombosis Atheroembolic disease

Infections

Acute pyelonephritis

CLINICAL ISSUES Epidemiology Incidence

Prerenal causes: 55-60% Renal parenchymal diseases: 35-40% Postrenal causes: < 5% AKI in hospitalized patient: 3-7% Age All ages are affected Etiology varies according to age

Presentation

Glomerular diseases

Nephritic/nephrotic syndrome Increased creatinine Oliguria/anuria Microangiopathic hemolytic anemia Thrombocytopenia systemic manifestations: Fever, arthralgias, flu-like symptoms Other organ involvement: Upper respiratory tract, central nervous system, lung, heart Tubular/interstitial Oliguria/anuria

Key Facts Terminology

Sudden sustained decline of glomerular filtration rate (GFR) associated with uremia, fall in urine output, and serum creatinine (SCr) increase

Etiology

Crescentic glomerulonephritis: ANCA-related small vessel vasculitis, anti-GBM crescentic glomerulonephritis, immune complex-related glomerulonephritis Acute postinfectious glomerulonephritis Thrombotic microangiopathy (TMA) Hypersensitivity reaction: Antibiotics, nonsteroidals, protein supplements, proton pump inhibitors Systemic disorders: Hypotension, hypovolemia, sepsis, rhabdomyolysis, post surgery

Hyaline, granular, pigmented casts in urine Fever in case of infections Creatinine increase Vascular ARF Eosinophilia Hypertension Skin petechial hemorrhages

Laboratory Tests Serum/blood

Serum creatinine Blood urea nitrogen (BUN) Antineutrophil cytoplasmic antibodies (ANCA/PR3, MPO) Antiglomerular basement membrane antibodies (anti-GBM) Antinuclear antibodies (ANA) Cryoglobulins Complement (C3, C4) SPEP/immunofixation Antistreptolysin antibody (ASO) Complete blood count (CBC) Electrolytes: Na, K, Ca, HCO, Cl, PO Urinalysis Microscopic examination for crystals, casts, cells Eosinophil count Urine protein electrophoresis (UPEP)

Treatment Drugs

Hypertensive medication Diuretics Immunosuppressors in case of glomerulonephritis Renal replacement therapy Hemodialysis, peritoneal dialysis Plasma exchange

Prognosis

Mortality rate in hospitalized patients ~ 21.3%; varies depending on etiology

Vascular: Renal vein or artery thrombosis, atheroembolic disease

Infections: Acute pyelonephritis

Clinical Issues

Prerenal causes: 55-60% Renal parenchymal diseases: 35-40% Postrenal causes: < 5% AKI in hospitalized patient: 3-7% All ages are affected, and etiology varies according to age

Microscopic Pathology

Microscopic findings vary according to processes causing renal failure

Long-term prognosis varies depending on cause and clinical setting, as well as pre- and post-AKI kidney function Recovery can occur Progression to end-stage renal disease is a risk in older patients with comorbidities Risk factors for poor outcome Male gender Advanced age Oliguria Creatinine > 3 mg/dL at presentation More severe renal injury Failure involving other organs

Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE

IMAGE FINDINGS Ultrasonographic Findings

Enlarged or normal-sized kidneys Vascular obstruction of vein or artery can be detected Pyelocalyceal system dilatation in case of obstruction

CT Findings

CT angiography useful to detect artery or vein occlusions

MACROSCOPIC FEATURES External Examination

Generalized edema, palpable purpura (vasculitis) Blood in mouth (pulmonary renal syndome: AntiGBM or ANCA)

Pallor, hemorrhagic shock (ATN)

Internal Examination Pleural effusions Ascites

Organ Examination

Gross examination of kidney

Remove fat for accurate weight Bisect kidneys in antero/posterior (coronal) plane

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE Measurement of cortex and medulla Assessment of cortex and medullary pyramids and pelvis Opening of calyces major and minor Tissue allocation Light microscopy

Sample from cortex and medulla should be submitted in formaldehyde from each kidney

H&E, PAS, trichrome, and Jones silver stains requested Immunofluorescence

Sample from cortex (2-3 mm thickness) snap frozen or placed in Michel or Zeus transport media should be saved

In case of glomerular diseases stains with IgG, IgA, IgM, C3, C1q, fibrinogen, and light chains should be requested Electron microscopy

Sample from cortex 2 x 3 mm cubes placed in glutaraldehyde should be saved and submitted for examination in cases of glomerular diseases Kidney gross appearance according to disease processes Glomerular diseases

Enlarged kidney with petechial hemorrhage

Extensive cortical necrosis in TMA Tubular diseases

Enlarged pale kidney

Swollen appearance and bulging from capsule

Widened cortex

Accentuation of cortico/medullary junction

Darker medulla Interstitial diseases/pyelonephritis

Enlarged kidney

Yellow or white microabscesses on the surface

Pale streaks extending from medulla into cortex

Mucosa of pyelocaliceal system show edema and erythema; may be covered by purulent material Vascular diseases

Malignant hypertension: Enlarged/normal size/ small kidney, chronic arterionephrosclerosis changes may be present; petechial hemorrhage flea-bitten appearance

Renal vein thrombosis: Enlarged kidney with vascular congestion; thrombus identified in vein and venules

Renal artery thrombosis: Thrombus in main renal artery and branches; renal artery stenosis and atheromatous plaque may be present; wedge peripheral infarcts

Atheroembolic disease: Cortical wedge infarcts when large artery involved

MICROSCOPIC PATHOLOGY Histologic Features Glomerular diseases

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Crescentic glomerulonephritis

ANCA related: Glomerular tuft fibrinoid necrosis; crescents; variable degree of interstitial inflammation; tubular injury

Anti-GBM crescentic glomerulonephritis: Glomerular tuft fibrinoid necrosis; crescents; variable degree of interstitial inflammation; tubular injury

Immune complex glomerulonephritis: Glomerular tuft fibrinoid necrosis; crescents; variable degree of interstitial inflammation; tubular injury Acute postinfectious glomerulonephritis

Enlarged glomeruli with endocapillary proliferation and numerous intracapillary neutrophils Thrombotic microangiopathy

Acute: Bloodless glomeruli, fibrin thrombi, glomerular capillary congestion and neutrophilic accumulation; mesangiolysis; arterioles and small arteries may contain fibrin thrombi Tubular diseases Acute tubular necrosis

Ischemic: Tubular epithelial cell damage in multiple, patchy segments of proximal tubule; breaks in tubular basement membranes; luminal casts (hyaline, granular)

Toxic: Extensive tubular epithelial cell necrosis in proximal tubules Cast nephropathy

Intratubular casts positive for light chain (75%) within distal tubules; with pale (on PAS) fractured appearance associated with inflammatory or giant cell reaction; mixed interstitial inflammation Acute phosphate nephropathy

Calcium phosphate crystals within tubular lumens with basophilic/purple color on H&E stain; not polarizable; mild interstitial inflammation; fibrosis and tubular atrophy; glomeruli not involved Bile (bilirubin) cast nephropathy

Bile casts in distal tubules; acellular and greenishtinged brown on H&E; green in Hall stain; tubular injury Oxalate nephropathy

Intratubular oxalate crystals with fan-like or irregular shapes and translucent on H&E stain; birefringent under polarized light; tubular injury; interstitial inflammation in fibrotic areas Rhabdomyolysis

Tubular epithelial injury, hyaline, granular and pigmented (hemoglobin/myoglobin) casts; interstitial edema; glomeruli are spared Intersitial diseases Acute interstitial nephritis: Mixed interstitial inflammation with frequent eosinophils; tubulitis; interstitial edema; multinucleated giant cells; nonnecrotizing granulomas Acute pyelonephritis: Neutrophilic interstitial inflammation with neutrophilic casts; interstitial edema Vascular diseases Malignant hypertension: Mucoid intima change; fibrinoid necrosis involving arterioles; corrugation/ reduplication of GBM; "onion skin" change in arterioles Renal vein thrombosis: Organized thrombus within renal vein and venules; glomerular capillary and

peritubular capillary congestion; neutrophilic margination; interstitial edema and hemorrhage Renal artery thrombosis: Cortical necrosis; interstitial hemorrhage Atheroembolic disease: Elongated cholesterol clefts in small arteries (100-200 nm in diameter) &/or glomerular capillaries; clefts may be surrounded by debris and fibrin or englobed by macrophages or giant cells Cortical necrosis Multifactorial etiology Multifocal or diffuse coagulative necrosis of cortex with glomerular and tubular involvement Thrombi may be identified in vasculature

ANCILLARY TESTS Immunohistochemistry

DIFFERENTIAL DIAGNOSIS Acute Tubular Necrosis Autolysis

Widespread tubular degenerative changes Pyknosis of tubular epithelial cell nuclei Detachment of tubular epithelial cells

REPORTING CRITERIA Final Report Should Include

Etiology of ARF and complications Effects in other organs Whether it was cause of death or contributing factor

SELECTED REFERENCES 1.

Myoglobin immunostain useful identifying casts in rhabdomyolysis

von Kossa stain highlights phosphate crystals

Immunofluorescence Glomerular diseases

ANCA related: No or minimal deposits Anti-GBM crescentic glomerulonephritis: Linear IgG deposits Immune-complex glomerulonephritis: Deposits of IgG, IgA, IgM, C3, C1q, and light chains in subendothelial, mesangial, &/or subepithelial distribution Acute postinfectious glomerulonephritis: Immunecomplex type deposits positive for C3 and in lesser intensity for IgG or IgM Thrombotic microangiopathy: Fibrinogen stain is seen in thrombi; nonspecific trapping of IgM and C3 in mesangium

4. 5.

Electron Microscopy Glomerular diseases

ANCA related: No or minimal deposits Anti-GBM crescentic glomerulonephritis: No deposits Immune-complex glomerulonephritis: Electrondense deposits in subendothelial, mesangial, &/or subepithelial distribution Acute postinfectious glomerulonephritis: Electrondense deposits in subendothelial, mesangial, &/or subepithelial distribution (hump-like configuration) Thrombotic microangiopathy: Fibrin tactoids, lamina rara interna expansion, mesangiolysis Tubular diseases Rhabdomyolysis: Casts containing electron-dense granules Vascular diseases Malignant hypertension: Expansion of lamina rara interna and mesangial interposition

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Ford SL et al: Histopathologic and clinical predictors of kidney outcomes in ANCA-associated vasculitis. Am J Kidney Dis. 63(2):227-35, 2014 Hellmark T et al: Diagnosis and classification of Goodpasture’s disease (anti-GBM). J Autoimmun. 48-49:108-12, 2014 Jennette JC et al: Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol. 10(8):463-73, 2014 Li Z et al: Clinical and pathological features of acute kidney injury in children. Ren Fail. 36(7):1023-8, 2014 Muriithi AK et al: Biopsy-proven acute interstitial nephritis, 1993-2011: a case series. Am J Kidney Dis. 64(4):558-66, 2014 Muriithi AK et al: Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney Int. Epub ahead of print, 2014 Tang X et al: Acute and chronic kidney injury in nephrolithiasis. Curr Opin Nephrol Hypertens. 23(4):385-90, 2014 Tanna A et al: Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors. Nephrol Dial Transplant. Epub ahead of print, 2014 Valluri A et al: Acute tubulointerstitial nephritis in Scotland. QJM. Epub ahead of print, 2014 Nasr SH et al: Clinicopathologic correlations in multiple myeloma: a case series of 190 patients with kidney biopsies. Am J Kidney Dis. 59(6):786-94, 2012 Hutchison CA et al: The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol. 8(1):43-51, 2011 Williamson SR et al: A 25-year experience with pediatric anti-glomerular basement membrane disease. Pediatr Nephrol. 26(1):85-91, 2011 Kocovski L et al: Can renal acute tubular necrosis be differentiated from autolysis at autopsy? J Forensic Sci. 54(2):439-42, 2009 Markowitz GS et al: Acute phosphate nephropathy. Kidney Int. 76(10):1027-34, 2009 Iwasa S et al: Autopsy case of microscopic polyangiitis with crescentic glomerulonephritis and necrotizing pancreatitis. Pathol Int. 55(8):520-3, 2005 Herrera GA et al: Renal pathologic spectrum in an autopsy series of patients with plasma cell dyscrasia. Arch Pathol Lab Med. 128(8):875-9, 2004

Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE

Variant Microscopic Features (Left) In this case of ANCArelated necrotizing crescentic glomerulonephritis, several glomeruli show cellular crescents , and there is inflammatory infiltrate in the interstitium , and numerous red blood cell casts are seen within tubules . (Right) In this case of ANCA-related necrotizing crescentic glomerulonephritis, a large circumferential cellular crescent admixed with fibrin is seen with collapse of the capillary loops .

(Left) In ANCA-related necrotizing crescentic glomerulonephritis, areas of fibrinoid necrosis and crescents can be identified. There is no significant proliferation in the portion of uninvolved glomerulus, which is different from immune complex crescentic glomerulonephritis. (Right) In ANCA-associated necrotizing crescentic glomerulonephritis, arteritis is an occasional finding, as is shown in this case, where extensive fibrinoid necrosis of the interlobular artery is seen.

(Left) IgA nephropathy shows a bright granular staining in mesangium for IgA by immunofluorescence. The staining may be dominant, or codominant with other immunoglobulins (IgG or IgM). C3 and light chain staining are also present. (Right) Electron microscopy shows mesangial electrondense deposits , usually attached to paramesangial basement membranes.

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Gross and Microscopic Features (Left) In acute postinfectious glomerulonephritis, there is marked endocapillary hypercellularity with lobular accentuation and presence of numerous neutrophils within the capillary lumina, as well as swollen endothelial cells. (Right) On Jones silver stain, the endocapillary proliferation is evident, and no significant changes are seen in the glomerular basement membranes. Frequent neutrophils are present .

(Left) Gross specimen from patient with hemolytic uremic syndrome show multiples areas of hemorrhage in the surface of the kidney as well as areas of white coloration corresponding to cortical infarcts . (Right) Thrombotic microangiopathy in Hemolytic uremic syndrome shows extensive fibrin thrombi in glomerular capillaries at the vascular pole. Thrombi may also involve small arteries.

(Left) Cortical necrosis is characterized by glomerular necrosis and acute tubular necrosis . This process may be secondary to obstetric complications such as abruptio placenta, placenta previa, septic abortion, etc. Other etiologies include transfusion reactions, thrombotic microangiopathy, shock, and antibody-mediated rejection. (Right) On silver stain in this case of cortical necrosis, the glomerulus appears congested and only the GBM and TBM are preserved.

Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE

Variant Microscopic Features (Left) Acute tubular injury is characterized by extensive flattening of tubular epithelial cell lining , dilatation of the tubular lumina, and presence of proteinaceous material within tubular lumina. Interstitial inflammation is not seen, and only inflammatory cells within peritubular capillaries may be present. (Right) In acute phosphate nephropathy, there is tubular epithelial injury , and numerous calcium phosphate crystals are present in tubular lumina .

(Left) Bile (bilirubin) casts are seen as brownish casts with slight green tinge with associated acute tubular injury with flattened epithelial cell lining . (Right) Bile (bilirubin) casts are seen as distinctly green with special stain for bilirubin (Hall stain).

(Left) In acute renal failure caused by ethylene glycol, there is extensive acute tubular injury with associated calcium oxalate crystals which are clear and may not be discernible by light microscopy . (Right) Calcium oxalate crystals are seen under polarized light as birefringent polarizable fanshaped crystals .

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Variant Microscopic Features (Left) A case of acute interstitial nephritis caused by drug-induced hypersensitivity reaction shows extensive interstitial edema with associated mixed interstitial infiltrate containing mononuclear cells (lymphocytes, plasma cells, macrophages) and eosinophils. (Right) High-power view shows acute interstitial nephritis with scattered interstitial eosinophils in a background of interstitial edema and tubular injury characterized by flattening of epithelial cells .

(Left) In this case of acute pyelonephritis, the kidney is enlarged and swollen. There are diffuse white streaks along the major and minor calyces that correspond to collecting ducts filled with purulent material. (Right) Section shows marked inflammatory infiltrate composed of mononuclear cells with numerous neutrophils as well as presence of neutrophilic casts , which are characteristic of acute pyelonephritis. Interstitial edema is also present.

Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE

(Left) The characteristic findings of acute pyelonephritis are neutrophils present in tubular lumina forming neutrophilic plugs as well as neutrophils invading tubular epithelium and interstitium . (Right) Papillary necrosis can occur in severe cases of acute pyelonephritis. In this case, there is coagulative necrosis with retention of medulla outlines but little cellular detail.

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE

Variant Microscopic Features (Left) In acute rhabdomyolysis, myoglobin casts are present within the tubules. They show a characteristic granular reddish-brown globular appearance , and there is associated acute tubular injury. (Right) The composition of the casts in rhabdomyolysis can be determined by immunohistochemistry for myoglobin. In this case, the cast is strongly positive for myoglobin .

(Left) In acute phase of malignant hypertension, there is marked mucoid degeneration characterized by basophilic change in the intima of arteries with reduction of the lumina. (Right) In malignant hypertension, the arterioles show intimal proliferation of myofibroblasts and lamination of internal elastic lamina with a characteristic onion skin appearance.

(Left) The arterioles in malignant hypertension may show areas of fibrinoid necrosis in the wall, which appears as a pink-red material . (Right) In malignant hypertension, the glomeruli usually show ischemic appearance and may also show fibrin thrombi ; however, glomeruli are not the dominant site of injury.

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Gross and Microscopic Features (Left) Gross image in a case of thromboembolization in the kidney shows areas of cortical hemorrhage alternating with white areas that correspond to ischemic infarcts. Acute embolization may occur from atherosclerotic lesions. (Right) Atheroembolization is characterized by the presence of elongated clefts of cholesterol in the lumina of small arteries (100-200 m in diameter). There may be associated inflammatory reaction surrounding clefts.

(Left) In renal vein thrombosis, the kidney shows enlargement and swelling with extensive hemorrhage involving cortex and medulla. Thrombosis of renal vein may occur in nephrotic syndrome, anti-phospholipid antibody syndrome, malignancies, infections, trauma, etc. (Right) In this case of renal vein thrombosis, the glomerular capillaries are congested with marginating neutrophils in the lumina. Tubular epithelial cell necrosis and interstitial hemorrhage are also present.

(Left) Autolysis is a common finding in autopsy kidneys, and it is difficult to differentiate from acute tubular injury; however, it is a more diffuse process with detachment of epithelial cells from tubular basement membranes and nuclear pyknosis . (Right) On PAS stain, the separation of tubular epithelial cells from the basement membranes is more evident. The degree of autolysis varies depending of post mortem interval, cooling time, and body mass.

Organ System Approach to Autopsy: Sudden and Unexpected Death

ACUTE RENAL FAILURE

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ADRENAL INSUFFICIENCY

The relationship between hypothalamus, pituitary, and adrenal gland is shown. Various stimuli affect the anterior pituitary (including corticotropin-releasing hormone [CRH], antidiuretic hormone [ADH], and cytokines), leading to release of adrenocorticotrophic hormone (ACTH). Under the influence of ACTH, the adrenal glands increase secretion of various steroid-based hormones including cortisol and androgens. Negative feedback loops also inhibit the release of ACTH and the hormones produced by the adrenal glands. Abnormal or inappropriate inhibition of these adrenal hormones leads to adrenal insufficiency.

TERMINOLOGY Synonyms

Adrenal hypofunction Addison disease

ETIOLOGY/PATHOGENESIS Primary Causes

Primary chronic adrenocortical insufficiency (Addison

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disease) Most often due to autoimmune adrenalitis Autoimmune adrenalitis 50% of cases associated with other autoimmune endocrine disorder Esp. thyroid, parathyroid disease May be part of "autoimmune polyglandular syndromes"

Almost complete loss of adrenal cortical cells achieved before symptoms manifest "Tipping point" may occur under stressful conditions (basal needs can be met, but stress levels cannot) Presumed autoantibody to adrenal cortical cell epitopes Adrenal hemorrhage Often associated with sepsis due to bacterial infection Causative organisms Neisseria meningitidis Gram-positive cocci (Staphylococcus and Streptococcus) Haemophilus influenzae Klebsiella spp. Pseudomonas spp. Opportunistic fungi: Candida spp. Waterhouse-Friderichsen syndrome Bilateral adrenal hemorrhage (massive)

Key Facts Etiology

Autoimmune adrenalitis (Addison disease) Adrenal hemorrhage (Waterhouse-Friderichsen syndrome) Often associated with sepsis due to bacterial infection Tuberculosis Congenital defects Adrenal agenesis Congenital adrenal hypoplasia Adrenoleukodystrophy Adrenal metastasis Iatrogenic (rapid steroid withdrawal) Postpartum pituitary infarction (Sheehan syndrome)

Clinical Issues

Acute insufficiency (Addisonian crisis) More common in children Classically due to Neisseria meningitidis sepsis Other noninfectious etiologies (rare) Cardiogenic shock Severe burns Hypercoagulable states (including pregnancy) Excessive anticoagulation or thrombolytic therapy Hypothermia Tuberculosis Most common cause of adrenalitis worldwide, but rare in developed countries 6% of patients with active infection Congenital defects Adrenal agenesis 10% of unilateral renal agenesis also ipsilateral adrenal agenesis Congenital adrenal hypoplasia Association with anencephaly and congenital hypothalamus-pituitary axis anomalies X-linked adrenal hypoplasia congenita (DAX1 mutation) Familial glucocorticoid deficiency (mutations of ACTH receptor) Adrenoleukodystrophy Fatty acid metabolism disorder (very long chain fatty acids [VLCFA]) Clinically and genetically heterogeneous Signs and symptoms include myeloneuropathy (defect in myelination) and adrenal insufficiency Rare "Addison only" form Adrenal metastasis Primary (carcinomas): Lung, breast, upper GI, liver, renal, ovarian Non-carcinomas: Lymphoma, sarcoma Bilateral in 50% 80-90% replacement of adrenal tissue before symptoms manifest Genetic Autoimmune polyendocrinopathy syndrome 1 (AIRE gene on 21q22)

Back, abdominal &/or leg pain Severe vomiting and diarrhea (volume depletion) Hypotension, shock Altered mental status (even coma) Hyperkalemia

Macroscopic Pathology Adrenal glands

Glands initially normal size (4-7 g)

Marked bilateral atrophy in end stages Can weigh < 2 g

Microscopic Pathology Autoimmune adrenalitis

Lymphoplasmacytic inflammation Medulla is relatively preserved and can extend to capsule

Autoimmune polyendocrinopathy syndrome 2 (polygenic) Iatrogenic Rapid withdrawal of corticosteroids

Secondary Causes

Secondary chronic adrenocortical insufficiency

Organ System Approach to Autopsy: Sudden and Unexpected Death

ADRENAL INSUFFICIENCY

Most commonly from hypothalamic suppression due to long-term corticosteroid use No hyperpigmentation or electrolyte imbalances Postpartum pituitary infarction (Sheehan syndrome) Complication of massive hemorrhage during delivery Mechanism not completely understood (localized vasospasm?) 10% of cases without clinically recognized peripartum volume loss Acute: Liquefactive necrosis Chronic: Fibrotic replacement Pituitary "apoplexy": Similar to Sheehan syndrome, but infarction due to adenoma Partial or complete (pan) hypopituitarism Hypogonadism: 100% of cases Prolactin and growth hormone: 100% of cases Hypothyroidism: 90% of cases Hypocortisolism: 50% of cases Latency between event and symptoms varies widely (2 months to decades later)

CLINICAL ISSUES Presentation

Signs and symptoms

Chronic insufficiency Muscle weakness and fatigue Weight loss and decreased appetite Hyperpigmentation of skin Hypotension, lightheadedness Salt craving Electrolyte disturbances: K, Na Hypoglycemia

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ADRENAL INSUFFICIENCY Nausea, vomiting, diarrhea Myalgias, arthralgias Depression Body hair loss or sexual dysfunction (in women) Acute insufficiency (Addisonian crisis) Back, abdominal, &/or leg pain Severe vomiting and diarrhea (volume depletion) Hypotension, shock Altered mental status (even coma) Hyperkalemia

Laboratory Tests

Acute inflammation Exclude renal vein branch thrombosis Tuberculosis Chronic inflammation, giant cells, and caseation Granulomas may be less developed than in other sites Subcapsular granulation tissue and calcifications in older lesions

SELECTED REFERENCES 1.

Adrenocorticotrophic hormone (ACTH) (antemortem)

Can be used to distinguish between patients with Primary adrenal insufficiency ( ACTH, cortisol) Secondary causes (e.g., pituitary) (nl or ACTH, cortisol)

IMAGE FINDINGS

3. 4.

CT Findings

Adrenal gland enlargement Hemorrhage Metastatic tumor Adrenal gland atrophy

MACROSCOPIC FEATURES External Examination

Hyperpigmentation: Addison disease Hair distribution: Addison disease Ecchymoses, petechiae: Adrenal hemorrhage

Internal Examination

Pituitary necrosis, fibrosis Cardiomyopathy Metastatic malignancy Gonadal atrophy Renal pallor

Organ Examination Adrenal glands

Glands initially normal size Normal weight range: 4-7 g each (with fat removed) Marked bilateral atrophy in end stages Can weigh < 2 g

MICROSCOPIC PATHOLOGY Histologic Features

Autoimmune adrenalitis

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Lymphocytic and lymphoplasmacytic inflammatory infiltrate Cortical cell necrosis and loss Medulla is relatively preserved and can extend to capsule Adrenal hemorrhage Recent hemorrhage Loss of cortical parenchymal cells

Marti JL et al: Spontaneous adrenal hemorrhage with associated masses: etiology and management in 6 cases and a review of 133 reported cases. World J Surg. 36(1):75-82, 2012 Sethuraman C et al: Bilateral absence of adrenal glands: a case series that expands the spectrum of associations and highlights the difficulties in prenatal diagnosis. Fetal Pediatr Pathol. 30(2):137-43, 2011 Guarner J et al: Adrenal gland hemorrhage in patients with fatal bacterial infections. Mod Pathol. 21(9):1113-20, 2008 Dkmeta HS et al: Characteristic features of 20 patients with Sheehan’s syndrome. Gynecol Endocrinol. 22(5):279-83, 2006 Lam KY et al: Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospital. Clin Endocrinol (Oxf). 56(1):95-101, 2002 Lack EE et al: Embryology, developmental anatomy, and selected aspects of non-neoplastic pathology. In Pathology of the Adrenal Glands. New York: Churchill Livingstone. 1-74, 1990 Petri M et al: Addison’s adrenalitis. Studies on diffuse lymphocytic adrenalitis (idiopathic Addison’s disease) and focal lymphocytic infiltration in a control material. Acta Pathol Microbiol Scand A. 79(4):381-8, 1971

Gross, Radiologic, and Microscopic Features (Left) Unilateral hemorrhage of adrenal gland is present on the right. Note the discrepancy in size between the 2 adrenals due to massive hemorrhage . The left adrenal gland is normal size for age in this neonate. (From DP: Nonneoplastic Pediatrics.) (Right) This gross photograph on an adrenal gland at autopsy shows hemorrhage into the interior of the gland. A thin rim of yellow adrenal cortex remains .

(Left) This low-magnification view of an adult adrenal gland at autopsy shows diffuse hemorrhage and complete loss of the normal histoarchitecture. The patient died from severe septic shock. (Right) At higher magnification, hemorrhage and inflammation are apparent. There is a complete loss of recognizable adrenal cortical cells, with only a few ghost outlines remaining.

Organ System Approach to Autopsy: Sudden and Unexpected Death

ADRENAL INSUFFICIENCY

(Left) This axial CT scan (antemortem) shows massive bilateral adrenal metastases from lung cancer that resulted in adrenal insufficiency. (From DI: Genitourinary) (Right) Metastatic lung carcinoma is shown, forming a dark hemorrhagic nodule in the adrenal gland. A thin rim of adrenal cortex is still present. The kidney (distorted by the mass) can also be seen.

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ADRENOCORTICAL EXCESS

This illustration shows the location of adrenal gland atop upper pole of kidney. Note adrenal cortical adenoma . Adenomas are a common cause of adrenocortical excess. (From DP: Pediatric Neoplasms.)

TERMINOLOGY Hypercortisolism: State of glucocorticoid excess

ETIOLOGY/PATHOGENESIS Types

Hypercortisolism

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Primary adrenal neoplasms (most typically adrenal cortical carcinoma)

Definitions

Cushing syndrome Aldosteronism: State of mineralocorticoid excess Adrenogenital syndrome(s): State of adrenal androgen excess

A dominant nodule of adrenal cortex is seen in a patient with adrenocortical hyperplasia. Additional, smaller nodules were scattered throughout the remaining gland. (Courtesy F. Shakil, MD.)

Can result from endogenous overproduction or exogenous sources Adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma Adrenal cortical hyperplasia Primary adrenal neoplasms (adenoma vs. carcinoma) Ectopic ACTH-producing neoplasms elsewhere in body (paraneoplastic) Aldosteronism Can result from endogenous overproduction of aldosterone (primary or secondary) or, less commonly, ingestion of certain substances Bilateral adrenal cortical hyperplasia Primary adrenal neoplasms (cortical adenoma): Conn syndrome Excessive ingestion of licorice compounds Secondary causes: Renal artery stenosis, diuretic abuse Adrenogenital syndrome Can result from inborn errors in enzymes involved in steroid production or from associated adrenal cortical neoplasms Congenital adrenal hyperplasia (CAH) (21hydroxylase deficiency)

CLINICAL ISSUES Presentation

Hypercortisolism

Fat redistribution (centripetal) Moon facies, wasting of arms/legs Skin changes (striae, ecchymoses) Menstrual irregularity Myopathy (proximal weakness) Osteoporosis Aldosteronism Refractory hypertension, hypokalemia Adrenogenital syndrome Signs and symptoms depend on which enzyme is affected and level of altered enzyme activity Absent cortisol (due to complete absence of 21-hydroxylase) salt-wasting syndrome + virilization Malignant adrenal neoplasms: Mixed picture of androgen excess hypercortisolism Adrenal tumors associated with virilization in children are often malignant Most sporadic; increased risk with Li Fraumeni, Beckwith-Wiedemann syndromes

Laboratory Tests

Primary aldosteronism: aldosterone, renin

MACROSCOPIC FEATURES External Exam

Centripetal obesity with muscle wasting of extremities, moon facies, buffalo hump

Abdominal striae, acne, ecchymoses, thinning of skin Hirsutism, virilization

Key Facts

CAH (21-hydroxylase deficiency) Primary adrenal neoplasms (most typically adrenal cortical carcinoma)

Etiology

Hypercortisolism

ACTH-secreting pituitary adenoma Adrenal cortical hyperplasia Primary adrenal neoplasms (adenoma vs. carcinoma) Ectopic ACTH-producing neoplasms elsewhere in body (paraneoplastic) Aldosteronism Bilateral adrenal cortical hyperplasia Primary adrenal neoplasms (cortical adenoma): Conn syndrome Excessive ingestion of licorice compounds Secondary causes: Renal artery stenosis, diuretic abuse Adrenogenital syndrome

Macroscopic Pathology Pituitary gland

ACTH-secreting adenoma in patients with Cushing syndrome Cardiovascular Left ventricular hypertrophy, secondary to hypertension (adrenocortical excess) Musculoskeletal Cushing myopathy (wasting), osteoporosis

Ambiguous genitalia (fetal autopsy)

Benign neoplastic proliferation of large cortical cells with abundant, pale-staining, lipid-rich, vacuolated cytoplasm Round, regular nuclei typically resembling cells of zona fasciculata Occasional pleomorphism ("endocrine atypia") Mitosis rare or absent Functioning and nonfunctioning adenomas essentially indistinguishable by morphology Cortical carcinoma Tumor cells resemble normal adrenal cortex but more pleomorphism and hyperchromasia (anaplasia) Trabecular, alveolar, or solid patterns Multinucleated neoplastic cells may be seen Numerous mitoses (including atypical mitoses) Cortical atrophy Cortical thinning (especially zona fasciculata and reticularis) Loss of cytoplasmic lipid (more eosinophilic cytoplasmic appearance)

Internal Exam Adrenal gland

Assess cortical & medullary thicknesses, nodularity, masses, atrophy Adrenal cortical hyperplasia: Bilateral, diffuse, nodular (micro- or macronodular) cortical hyperplasia Adrenal cortical adenoma: Solitary, unilateral, cortical nodular lesion; (usually < 5 cm) Adrenal cortical carcinoma: Rare malignant adrenal neoplasm; large, irregular, invasive massive with hemorrhage; often >100 g and > 10 cm in diameter Pituitary gland ACTH-secreting adenoma in patients with Cushing syndrome Cardiovascular Left ventricular hypertrophy, secondary to hypertension (adrenocortical excess) Other end-organ effects of hypertension (kidneys, aorta, white matter changes) Musculoskeletal Cushing myopathy (wasting), osteoporosis Exclude other solid organ malignancy (paraneoplastic syndrome)

MICROSCOPIC PATHOLOGY Histologic Features

Adrenal gland morphology

Cortical hyperplasia (diffuse/micro- or macronodular) Hyperplasia of cortical cells seen in diffuse or nodular pattern Lipid-depleted cells with compact, eosinophilic cytoplasm or lipid-rich cells Occasional isolated hyperplasia of specific cortical zones may be identified Cortical adenoma

Organ System Approach to Autopsy: Sudden and Unexpected Death

ADRENOCORTICAL EXCESS

SELECTED REFERENCES 1.

Piaditis G et al: Progress in aldosteronism: a review of the prevalence of primary aldosteronism in pre-hypertension and hypertension. Eur J Endocrinol. 172(5):R191-203, 2015 Raff H et al: Cushing’s syndrome: from physiological principles to diagnosis and clinical care. J Physiol. 593(3):493-506, 2015 Lloyd RV et al. Atlas of NonTumor Pathology: Endocrine Diseases (Fascicle 1). Washington DC: American Registry of Pathology and the Armed Forces Institute of Pathology. 171-257, 2002

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Organ System Approach to Autopsy: Sudden and Unexpected Death

ADRENOCORTICAL EXCESS

Gross Features (Left) Yellow-orange cut surface of a large, circumscribed adrenal cortical adenoma is seen in a patient with Cushing syndrome. Uninvolved adrenal cortex is atrophic. (Courtesy P. Unger, MD.) (Right) Large (14.5 cm) adrenal cortical carcinoma is shown. The variegated cut surface is yellow-tan and coarsely lobulated with areas of hemorrhage , necrosis , and cystic degeneration . (Courtesy Y. Yusuf, MD.)

(Left) This adrenal gland shows renal cortical macronodular hyperplasia with multiple cortical nodules . Bilateral hyperplasia is seen in Cushing disease caused by pituitary adenoma. (From DP: Endocrine.) (Right) This pituitary gland shows a circumscribed lesion , consistent with adenoma. ACTH-producing adenomas are often grossly hemorrhagic . (From DP: Neuro.)

(Left) This lung mass was present in a patient with metastatic lung cancer who had features of Cushing syndrome clinically. Paraneoplastic ACTH production is a potential cause of cortisol excess. (From DP: Thoracic.) (Right) This aortic specimen from an autopsy of a patient with bilateral renal artery stenosis shows the characteristic features of fibromuscular dysplasia . Renal artery stenosis is a cause of secondary aldosteronism.

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Microscopic Features (Left) Diffuse and micronodular adrenal cortical hyperplasia is shown. In adults, cases of diffuse, bilateral adrenal cortical hyperplasia may result from an ACTHsecreting pituitary adenoma or, less commonly, by ectopic production of ACTH or CRH. (Right) On slightly higher magnification, nodular areas of hyperplasia show alternating areas of lipid-rich cortical cells and more eosinophilic lipiddepleted cells .

(Left) This high-power photomicrograph of a pituitary gland removed at autopsy from a patient with Cushing syndrome shows features of adenoma. There is cellular monotony. The cells form sheets rather than nests. (From DP: Neuro.) (Right) Cortical extrusion in a patient with nodular adrenal cortical hyperplasia is shown. The nodule is predominantly composed of cells with abundant, palestaining, lipid-rich cytoplasm, resembling cells of the zona fasciculata.

(Left) Adrenal cortical carcinoma shows pleomorphic, hyperchromatic cells with fairly compact, eosinophilic cytoplasm. Scattered cells show multilobulated nuclei . A fibrous band containing vascular channels is apparent , as is an area of necrosis . (Right) Adrenal cortical carcinoma shows broad trabecular growth pattern of neoplastic cells that are separated by delicate fibrous bands containing vascular channels . Areas of necrosis are apparent .

Organ System Approach to Autopsy: Sudden and Unexpected Death

ADRENOCORTICAL EXCESS

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Organ System Approach to Autopsy: Sudden and Unexpected Death

SEIZURE DISORDERS

Coronal slice of brain with tuberous sclerosis (TS) is shown with cortical tuber , subcortical tuber , and subependymal nodule . (Courtesy L.C. Ang, MD.)

TERMINOLOGY Definitions Seizure

Abnormal firing of neuron groups through uncontrolled excitation or loss of inhibition Can result in disruption of consciousness, involuntary movements, vocalizations, &/or loss of continence

ETIOLOGY/PATHOGENESIS Developmental Anomaly Congenital/genetic

Mesial temporal sclerosis (MTS) Hereditary disorders: Tuberous sclerosis (TS), SturgeWeber, mitochondrial disorders Congenital: Heterotopias, cortical dysplasias, lissencephaly, polymicrogyria

Infectious Agents Viral

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Herpesviridae (HSV, VZV, CMV) Enterovirus HIV Bacterial Septic emboli/abscess Spirochetes: Neurosyphilis, Lyme meningoencephalitis Mycobacterial Fungal Aspergillosis Cryptococcal Parasitic Protozoa: Toxoplasma Gondii, Trypanosoma brucei, Plasmodium falciparum (malaria) Neurocysticercosis

Mutation of LIS1 (neuronal migration gene) is implicated in 80% of lissencephaly, shown here. This brain demonstrates pachygyria (expanded gyri) and subcortical band heterotopia .

Most common acquired seizure etiology in Asia, Africa, Central and South America Other nematodes (Echinococcus, Schistosoma) Amoeba (Naegleria fowleri, Acanthamoeba species, Entamoeba histolytica) Prion Creutzfeldt-Jakob disease

Tumors/Masses

Space occupying, mass effect

Metabolic

Hypo-/hyperglycemia Hypoxemic-ischemic encephalopathy Ion imbalances Na, Na, Ca, Mg, NH4 Uremia Eclampsia

Toxic/Drugs

Cocaine, heroin, amphetamines Phencyclidine, MDMA (ecstasy) Tricyclic antidepressants, antihistamines, lithium Withdrawal from alcohol, narcotics, or barbiturates Organophosphates, nerve agent (VX, sarin)

Vascular

Arteriovenous malformation (AVM) and aneurysms Thrombotic thrombocytopenic purpura (TTP) Hematomas Infarction (acute or old)

Trauma

Contusions Hemorrhage

Alzheimer Disease

Especially in later stages of disease

Inflammatory Sarcoidosis

Key Facts Terminology

Abnormal firing neuron groups, either through uncontrolled excitation or loss of inhibition

Etiology

Congenital/genetic

Mesial temporal sclerosis (MTS) (idiopathic) Tuberous sclerosis Nodular or band heterotopias Cortical dysplasia Infections Viral Bacterial Fungal Parasitic Prion Metabolic

Rheumatoid Systemic lupus erythematosus

CLINICAL ISSUES Presentation

Simple or complex Partial or generalized (or secondarily generalized) New onset or chronic Note anticonvulsant use as there may be secondary neuropathological changes

Treatment

Surgical approaches

Focal resection for discrete epileptogenic focus Hemispherectomy for severe refractory seizures (e.g., Rasmussen, hemimeganencephaly) Callosotomy (transsection of corpus callosum) for atonic seizures and to prevent secondary generalization Drugs Clonazepam, phenobarbital, gabapentin Phenytoin, carbamazepine, lamotrigine (sodium channel blockade) Topiramate (inhibits effect of glutamate)

Prognosis

Depends on etiology and individual response to treatment

Cause of death

Terminal seizure (e.g., status epilepticus): Diagnosis of exclusion Secondary consequence (drowning, motor vehicle crash, fall)

IMAGE FINDINGS CT/MR

Mass lesions Enhancement (e.g., in encephalitis) Neuronal heterotopias

Hypo-/hyperglycemia Hypoxemic-ischemic encephalopathy Ion imbalances Drug Cocaine, heroin, amphetamines Withdrawal from alcohol, narcotics, or barbiturates Arteriovenous malformation (AVM) and aneurysms Thrombotic thrombocytopenic purpura (TTP)

Clinical Issues Cause of death

Terminal seizure (e.g., status epilepticus): Diagnosis of exclusion Secondary consequence (drowning, motor vehicle crash, fall)

Infarction Hippocampal atrophy and increased T2 signal in MTS Malformations/anomalies Atrophy (Alzheimer)

Angiography

Vasculitis, aneurysm, AVM

Organ System Approach to Autopsy: Sudden and Unexpected Death

SEIZURE DISORDERS

MACROSCOPIC FEATURES External Exam

Trauma from seizure

Contusions or lacerations to head, bite marks on tongue Signs of Sturge-Weber: Dark red "port-wine stain" of face, hemangioma Signs of TS: Pale "ash leaf" spots, leathery "shagreen patches" or reddish bumps (angiofibromas) Signs of intravenous drug abuse: Track marks, etc.

Internal Exam

Thorough examination of all organs for cause of death Skull fractures Central nervous system Dura and meninges Hemorrhage Excessive vascularity and calcifications (SturgeWeber) Meningitis (cloudy membranes) Surface of brain Contusions (plaques jaunes: Yellow-orange discoloration indicating old contusions), inferior frontal and temporal Uncal or cerebellar tonsillar herniation Congenital malformations: Porencephaly, polymicrogyria, tubers Atrophy suggestive of dementias Coronal 1 cm thick sections through cerebrum Tumors, infarction, hemorrhage Nodular or band heterotopias: Misplaced periventricular gray matter in nodules or bands

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SEIZURE DISORDERS Cortical dysplasia: Blurring of gray-white junction, expansion of gray matter Punctate hemorrhages: Indicative of TTP or septic emboli Multiple cysts: Toxoplasmosis or cysticercosis Hemorrhagic or necrotic temporal lobes: HSV encephalitis Infarction/necrosis of putamen (methanol), globus pallidus (carbon monoxide), or both (heroin, cocaine) Asymmetrical hippocampal atrophy: MTS Parasagittal slices through cerebellum Cerebellar atrophy: Long-term phenytoin use

MICROSCOPIC PATHOLOGY Histologic Features Infections

Bacterial: Septic emboli, neutrophils and microbes, Gram stain, rim of gliosis Viral: Inclusions, neuronophagia (neurons surrounded by microglia), lymphocytes Fungal: Granulomas, GMS, PAS, mucicarmine (Cryptococcus) Focal cortical dysplasia/tubers Disrupted cortical layering, clustering and columnar neuron arrays Loss of neuron polarity and balloon neurons (giant, sometimes multinucleated neurons) Tuberous sclerosis; also subependymal nodules and subependymal giant cell astrocytoma MTS Loss of neurons and gliosis in specific areas of Ammon horn in hippocampus, with double or widened layer of dentate neurons Metabolic Hyperammonemia/uremia: Alzheimer type 2 astrocytes (clear transparent nuclei, scant cytoplasm) abundant in basal ganglia Hypoxic-ischemic encephalopathy Shrunken, hypereosinophilic neurons with pyknotic nuclei (especially CA1 hippocampus and Purkinje cells) Therapeutic complication Cerebellar atrophy, loss of Purkinje cells with chronic phenytoin use

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features Death in patient with longstanding epilepsy

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Etiology Head trauma History of drug use Developmental delay (perinatal hypoxia, Lennox Gastaut) Systemic disease: Lupus, diabetes, malignancy, TTP, liver failure Liver failure, mitochondrial disorders AVM, tubers: Focal onset (partial simple)

MTS: Temporal lobe epilepsy (clinical) Travel, immunocompetency status for infections Confirm/establish cause of seizure disorder Focal brain lesion (cortical dysplasia, tubers, heterotopias, vascular lesions, masses) Developmental anomaly (MTS, Sturge-Weber, congenital anomalies) Systemic disease (remote hypoxia, metabolic, TTP, infection) Toxins/drugs (drugs of abuse, antidepressants, withdrawal symptoms) Determine role of seizure disorder in cause of death Signs of trauma (acute, subacute, old) Secondary consequence of seizure (drowning, motor vehicle crash) Therapeutic misadventure (surgical complication, medication side effect) Sudden death, suspected seizure-related Identify substrate lesion in brain or other metabolic cause of seizure activity Thoroughly exclude all other potential causes of sudden death Sudden death due to epilepsy is controversial diagnosis; requires very carefully consideration and exclusion of other possible causes

Pathologic Interpretation Pearls

Hypoxia/ischemia: "Red-dead" neurons Renal or hepatic failure: Alzheimer type 2 astrocytes in basal ganglia

If recent onset of behavioral change/dementia with seizures, consider autopsy with Prion disease protocol

REPORTING CRITERIA Cause of Seizures

Primary seizure disorder or other cause

Cause of Death

Whether seizure is primary cause of death or contributed to death through trauma, drowning, etc.

SELECTED REFERENCES 1. 2.

Nash TE: Parasitic diseases that cause seizures. Epilepsy Curr. 14(1 Suppl):29-34, 2014 Pollanen MS et al: Sudden unexpected death in epilepsy: a retrospective analysis of 24 adult cases. Forensic Sci Med Pathol. 8(1):13-8, 2012 Zhuo L et al: Sudden unexpected death in epilepsy: Evaluation of forensic autopsy cases. Forensic Sci Int. 223(1-3):171-5, 2012 Jensen L et al: Sudden death and the forensic evaluation of neurocutaneous syndromes. J Forensic Leg Med. 16(7):369-74, 2009 Leventer RJ et al: Malformations of cortical development and epilepsy. Dialogues Clin Neurosci. 10(1):47-62, 2008

Gross and Microscopic Features (Left) Neu-N stains neuronal nuclei, as seen here in the dentate gyrus of the hippocampus, showing dentate dispersal (a feature of MTS) with neurons radiating out from the usual tight band of the dentate . Loss of neurons in CA4 and CA1 with gliosis can also be seen. (Right) Old contusions are often seen where cortex abuts skull ridges as in the orbitofrontal cortex . Note the yellowbrown discoloration of cortex (plaques jaune) and underlying cavitation.

(Left) Neurocysticercosis (T. solium) is microscopically seen with a cyst containing degenerating scolex on H&E. Inflammation and calcification may result with disease progression. (Right) Periventricular nodular heterotopia is shown here as a gray matter nodule protruding into the lateral ventricle. These are often associated with MTS. The appearance is similar to the subependymal nodules of tuberous sclerosis, but heterotopias are larger and rarely calcify.

Organ System Approach to Autopsy: Sudden and Unexpected Death

SEIZURE DISORDERS

(Left) One feature of focal cortical dysplasia is the presence of "balloon" neurons with large nuclei and abundant cytoplasm, as shown here on H&E. (Right) Thrombotic thrombocytopenic purpura in the brain manifests as multiple petechial hemorrhages at the graywhite junction. This disease presents with seizures and neuropsychiatric disturbances as well as renal failure, rash, and hemolytic anemia.

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SUBDURAL HEMORRHAGE

An SDH spreads unilaterally between dura and arachnoid . Dural cells form outer granulation tissue in 7-10 days. An inner neomembrane forms after 3 weeks.

TERMINOLOGY Abbreviations

Subdural hematoma or hemorrhage (SDH)

ETIOLOGY/PATHOGENESIS Trauma

Severe head/spinal impact

Acute SDH Chronic SDH Often with parenchymal contusions Nonimpact diffuse axonal injury (DAI) Acceleration/deceleration injury No history of impact

Nontraumatic SDH Hematologic disease Coagulopathy Malignancy

Lesion Development Acute SDH

Venous (rarely arterial) blood collects between dura and outer arachnoid membrane Initially clotted blood forms Subacute SDH Clot liquefaction (over several days to 3 weeks) Chronic SDH Granulation tissue Rebleeding: Possible hematoma enlargement Neomembrane visible by 3 weeks

CLINICAL ISSUES

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Presentation

History of trauma: Traumatic brain injury (TBI)

Assault, fall, sports injury, motor vehicle accident

Axial CT of acute SDH in a patient post fall shows blood distribution similar to that shown in the previous image.

Other relevant history

Hematologic disease, anticoagulation, cirrhosis Brain or spine surgery, intracranial malignancy Alcoholism, chronic renal failure Symptoms (headache, nausea, mental status change) usually gradual in onset but progressive Pertinent antemortem data Glasgow coma score (GCS) CBC, PT, aPTT, INR, D-dimer, platelet count Imaging (CT or MR) Fractures, hematoma, neomembrane

Treatment

Acute SDH: Drainage brain reexpansion

Twist drill or burr-hole craniostomy with catheter drainage Decompressive hemicraniectomy for brain swelling Subacute/chronic SDH Surgical craniostomy with outer membranectomy Inner membranectomy avoided due to risk of brain herniation through membrane/skull defect Surgical complications Incomplete SDH evacuation with continued symptoms Rebleed (10-30%) Postoperative complications Seizures, intracerebral hemorrhage, epidural hematoma, pneumocephalus, intracerebral abscess Uncommon: Meningitis, skull osteomyelitis, acute SDH contralateral to drained chronic SDH (rapid decompression and tearing)

Prognosis

Spontaneous resolution infrequent Nontraumatic SDH

Primary disease often dictates prognosis

Traumatic SDH: Mortality rate ~ 50%

Surgery within 4 hours: Mortality rate 30-35%, functional recovery rate 55-65%

Key Facts Etiology

Traumatic

Impact and nonimpact diffuse axonal injury (DAI)

Hematologic disease Coagulopathy Malignancy

Clinical Issues

Glasgow coma score (GCS) CBC, PT, aPTT, INR, D-dimer, platelet count Imaging (CT or MR) Fractures, hematoma, neomembrane

Macroscopic Pathology Acute SDH

Venous (rarely arterial) blood collects between dura and outer arachnoid membrane

Surgery after 4 hours: Mortality rate 65-85%, functional recovery rate 7-15% Abnormal pupil light reaction on admission: survival and functional recovery rates High GCS: survival and functional recovery rates Cause of death Cerebral contusion (autonomic and metabolic dysfunction) Brain swelling and herniation Cerebral infarct/stroke (autonomic dysfunction) Particularly right insula (cardiac dysfunction) Diffuse axonal injury (sheer forces), especially brainstem

MACROSCOPIC FEATURES

Fibrinolysis clotted to liquid blood begins Chronic SDH Granulation tissue Rebleeding: Possible hematoma enlargement Neomembrane visible by 3 weeks

Microscopic Pathology Acute SDH

Intact erythrocytes, leukocytes No fibrin platelet lamination Chronic SDH Microscopically granulation tissue and hemorrhage identified as chronic SDH Outer neomembrane fibrosis (variable) Inflammatory cells (may include eosinophils)

After 7 10 days, granulation tissue established as neomembrane Microscopically granulation tissue and hemorrhage identified as chronic SDH Chronic SDH Outer neomembrane fibrosis (variable) Inflammatory cells (may include eosinophils) Granulation tissue Leaky macrocapillaries spontaneous rebleeding into central hematoma Inner neomembrane fibrosis (variable) Hematoma between neomembranes: Degenerating blood cells and strands of fibrin Fluid leakage from torn arachnoid through inner neomembrane hygroma formation within established neomembranes

Organ System Approach to Autopsy: Sudden and Unexpected Death

SUBDURAL HEMORRHAGE

Acute SDH

Clotted blood up to several days Initial solid blood may resolve

Subacute SDH

Mix of clotted blood and fluid Fluid by 3 weeks

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls

Important to exclude secondary causes of SDH

Occult metastatic malignancy microscopically Amyloid angiopathy Almost always associated with subarachnoidintracerebral hemorrhage

Chronic SDH

Variable-thickness neomembrane surrounding hematoma Outer neomembrane adjacent to dura Inner neomembrane adjacent to arachnoid Central hematoma variably liquefied Calcified chronic SDH (armored brain)

MICROSCOPIC PATHOLOGY Histologic Features Acute SDH

Intact erythrocytes, leukocytes No fibrin platelet lamination Subacute SDH (stage not reliably identified by histology)

SELECTED REFERENCES 1.

3. 4.

Walcott BP et al: Time interval to surgery and outcomes following the surgical treatment of acute traumatic subdural hematoma. J Clin Neurosci. 21(12):2107-11, 2014 Sim YW et al: Recent changes in risk factors of chronic subdural hematoma. J Korean Neurosurg Soc. 52(3):234-9, 2012 Ma YH et al: Management of chronic subdural haematoma. Lancet. 375(9710):195; author reply 195-6, 2010 Wen L et al: Spontaneous rapid resolution of acute subdural hematoma after head trauma: is it truly rare? Case report and relevant review of the literature. Ir J Med Sci. 178(3):367-71, 2009 Love S et al: Greenfield’s Neuropathology. London: Hodder Arnold, 2008

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SUBDURAL HEMORRHAGE

Gross and Microscopic Features (Left) An acute SDH is formed of clotted blood between the dura, here seen partially reflected , and the arachnoid. The acute SDH covers most of the right dorsolateral convexity of the brain, with some temporal lobe visible . (Right) H&E stain of acute SDH reveals only intact erythrocytes and leukocytes with no lamination that would be seen in other types of intracranial hemorrhage. A local coagulopathy is thought to prevent lamination by formed fibrin.

(Left) This dural cap’s internal surface has a thin neomembrane of a chronic SDH on its left side. The thinnest parts can be difficult to see. Neomembranes are adherent to the inner dura, unlike nonadherent postmortem blood collections after dissection. (Right) The left cerebrum under the chronic SDH shown at the left is compressed . Compression is not from the relatively thin neomembrane on the dural cap, but from liquefied blood that drained away during autopsy dissection.

(Left) This bilateral SDH over the cerebrum and cerebellum resulted from traumatic skull fractures. Note how cerebral gyri and cerebellar folia are hidden by the blood external to the arachnoid . Microscopy would be needed for classification as acute or chronic. (Right) Adherent chronic SDH (note the orange coloration often seen) is shown on the inner side of reflected dura and also adherent over the arachnoid in this patient with chronic myeloid leukemia.

Gross and Microscopic Features (Left) A patient with systemic lupus erythematosus was septic and died with a coagulopathy. A patchy SDH is adherent to the inner side of the spinal dura and to the arachnoid . The cauda equina is also seen . (Right) The neomembrane of a chronic SDH is adherent to the inner surface of this strip of the dural cap dissected for microscopic examination. One very thin area of the neomembrane has become partly dislodged during dissection. Other areas are hemorrhagic .

(Left) An extensive chronic SDH on the inner surface of the dural cap is partly a thin neomembrane and partly a hygroma . The fibrous nature of the hygroma membrane is seen by the gray-white color. Fluid in hygromas leaks from breaks in the outer arachnoidal membrane. (Right) Lowmagnification view shows dura with a thin, loosely adherent neomembrane . This chronic SDH is formed of granulation tissue that includes dilated, leaky macrocapillaries.

Organ System Approach to Autopsy: Sudden and Unexpected Death

SUBDURAL HEMORRHAGE

(Left) The outer membrane of a chronic SDH is formed of granulation tissue with leaky macrocapillaries and fibrosis . The hematoma is below the outer membrane. (Right) The inner membrane of a chronic SDH contains dilated capillaries , fibrosis, and chronic inflammation . Spontaneous resolution of a chronic SDH is not frequent. Clinical resolution below MR detection may occur, but the thin, neomembranous scar remains.

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SUBARACHNOID HEMORRHAGE

Traumatic SAH is present as part of contusions . Associated traumatic brain lesions include diffuse axonal injury in the corpus callosum and putamen contributing to a shift of midline structures.

TERMINOLOGY

CLINICAL ISSUES

Abbreviations

Presentation

Subarachnoid hemorrhage (SAH)

ETIOLOGY/PATHOGENESIS Trauma

Most common cause of SAH

Assault, fall, motor vehicle injury, spinal procedure

Nontraumatic

Most common cause: Ruptured saccular (berry) aneurysm Circle of Willis or posterior brain circulation Other vascular abnormalities Vascular malformation Arteriovenous (AV) malformation Cavernous angioma Moyamoya-like malformation Children: Sickle cell disease Adults: Atherosclerosis AV fistula or shunt Cerebral amyloid angiopathy Late pregnancy/puerperium Arterial aneurysm or AV malformation/fistula Reversible cerebral vasoconstrictive syndrome Cerebral venous sinus thrombosis

Pathogenesis Trauma

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SAH was present in this patient with shock and DIC. The gyri are obscured and blood fills many of the sulci without any blood present on the external side of the leptomeninges.

Ruptured subarachnoid vein(s) Subarachnoid arterial dissection/rupture Nontraumatic Ruptured aneurysm, vascular malformation Coagulopathy Vertebrobasilar artery dissection/rupture (spontaneous) Hemorrhagic stroke

Trauma

Traumatic SAH vasospasm and ischemia denote more severe injury Associated lesions: Contusion, subdural hematoma, diffuse axonal/diffuse vascular injury Nontraumatic Coagulopathy Hematologic/neoplastic disease Anticoagulation/antiplatelet therapy Headache, mental status change, neck stiffness, increased intracranial pressure Significant initial bleed "thunderclap" headache Complications Early anoxic brain injury Hypoxia, oxidative stress, inflammation Delayed cerebral injury (DCI) Vasospasm may occur 3-14 days post rupture, possibly late manifestation of early brain injury Focal neurologic deficits, cognitive change in 50% of patients 4-12 days after rupture Hydrocephalus Pertinent antemortem data Glasgow coma scale Computed tomography (CT), CT angiography, CT perfusion imaging Transcranial Doppler findings for cerebral blood flow velocity CBC, PT, aPTT, INR, D-dimer, platelet count

Treatment

Saccular aneurysm

Surgical clipping, endovascular embolization Nimodipine (calcium channel antagonist) DCI/ infarct rate; may mild hypertension AV malformation

Key Facts Etiology

Most common cause of SAH: Trauma (impact)

Rupture of subarachnoid veins Subarachnoid arterial wall hematoma/dissection Nontraumatic SAH: Ruptured saccular aneurysm, vascular malformation, arteriovenous fistula, spontaneous arterial wall hematoma/dissection Coagulopathy (primary disease, drug-related)

Nimodipine: Vasospasm and ischemia prevention Traumatic SAH prognosis: Related to associated lesions, general medical condition, autonomic compromise (e.g., cardiac function) Nontraumatic SAH prognosis Positive effect of nimodipine Cerebral infarct (poor outcome) Autonomic compromise

Clinical Issues

Macroscopic Pathology

neurologic deficits Vasospasm neurologic deficit (variable) Cerebral ischemia/infarction Traumatic SAH treatment: Surgical/medical approach Nontraumatic SAH treatment (ruptured aneurysm) Surgical clipping, endovascular embolization

Burr hole, craniotomy, hemicraniectomy Catheters, ventriculoperitoneal shunt tube Surgical clip, coils, stent, sponge material SAH over gyri, in sulci (relative amount) SAH filling subarachnoid cisterns (relative amount) Vascular rupture site, if identified

Headache, mental status change, neck stiffness, focal

Staged multimodal vessel obliteration (radiation, endovascular embolization, excision)

Prognosis Trauma

Depends on extent, comorbidities, autonomic compromise (e.g., cardiac function) Nontraumatic Saccular aneurysm rupture Endovascular coils morbidity/mortality rate compared to open surgical clip Improved prognosis: Early nimodipine use Poor prognosis: Infarct, vasospasm, autonomic dysfunction Cause of death Trauma Stroke, herniation Autonomic compromise Operative/treatment complications Nontraumatic Acute postrupture cerebral ischemia/infarct DCI/infarcts (25% of aneurysmal rupture deaths) Autonomic, metabolic dysfunction Underlying disease (coagulopathy, neoplasm)

IMAGE FINDINGS CT Findings Trauma

Intracranial blood, bony fractures

Evidence of surgical intervention

MACROSCOPIC FEATURES External Examination

Evidence of surgical intervention

Burr hole, craniotomy, hemicraniectomy Catheters, ventriculoperitoneal shunt tube

Internal Examination

SAH over gyri, extending into sulci SAH filling subarachnoid cisterns Vascular rupture site, if identified

May be within largest SAH area (epicenter)

Surgical clip, coils, stent, sponge material

MICROSCOPIC PATHOLOGY Histologic Features

Blood in subarachnoid space

Recent Resolving (pigment-laden macrophages) Bleeding source Ruptured saccular aneurysm Vascular malformation or fistula Cerebral amyloid angiopathy Contusion (trauma) Meningitis (acute/chronic inflammation)

SELECTED REFERENCES 1.

Nontraumatic

Ruptured cerebral arterial aneurysm: Location and amount of blood Early scan (within 24 hours of rupture) Cisternal SAH amount correlates with symptomatic vasospasm Enhancing intracranial/spinal lesions

Organ System Approach to Autopsy: Sudden and Unexpected Death

SUBARACHNOID HEMORRHAGE

2. 3.

Miller BA et al: Inflammation, Vasospasm, and Brain Injury after Subarachnoid Hemorrhage. Biomed Res Int. 2014:384342, 2014 Mrozek S et al: Biomarkers and acute brain injuries: interest and limits. Crit Care. 18(2):220, 2014 Lee Y et al: Current controversies in the prediction, diagnosis, and management of cerebral vasospasm: where do we stand? Neurol Res Int. 2013:373458, 2013

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SUBARACHNOID HEMORRHAGE

Gross and Microscopic Features (Left) This unfixed brain has scattered, small SAH . Brain sections with overlying leptomeninges taken carefully to avoid separation of cortex from leptomeninges are needed to document the SAH microscopically. (Right) SAH in this coronal section resulted from trauma (fall). The superficially sheared gyral crowns of the inferior frontal (orbital) cortex are obscured by neocortical hemorrhage and SAH. These are the classic finding of cortical contusions that can be confirmed microscopically.

(Left) Multiple contusions with associated SAH are seen in this brain from a patient who died following a trauma. Intraventricular hemorrhage and a small subdural hematoma are also present. (Right) Intraventricular hemorrhage within the cerebral aqueduct and distending the 4th ventricle is seen in this traumatically injured brain. SAH is also seen extending through the foramina of Luschka . SAH floods the posterior fossa and the spinal subarachnoid space.

(Left) SAH is seen after a craniotomy to relieve raised intracranial pressure for a large cerebral contusion . Cerebral hemorrhage and SAH now include traumatic brain injury, surgical contusion, and septic infarct. (Right) SAH and perivascular hemorrhages are seen in a medium-magnification photomicrograph of a recent cerebral contusion. Blood vessels within these spaces can be difficult to find.

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Radiologic, Gross, and Microscopic Features (Left) CT shows basal cistern SAH in the suprasellar cistern , interpeduncular cistern , and ambient cistern following the acute rupture of a saccular aneurysm of an anterior cerebral artery. The amount of SAH in these basal cisterns is used for clinical grading of an acutely ruptured saccular aneurysm of the brain. (Right) Rupture of a saccular aneurysm of a branch of the left middle cerebral artery has produced SAH that is relatively concentrated around the rupture site.

(Left) The circle of Willis has a ruptured saccular aneurysm of the right internal carotid artery with a surgical clip placed over the rupture site. Arachnoidal fibrosis is consolidated around the rupture/ surgical site . (Right) Leptomeningeal siderosis is helpful in identifying this small saccular aneurysm of an anterior cerebral artery, here stained with H&E. The very thin wall area may have been a site of minor blood leakage.

(Left) The saccular aneurysm has no internal elastic lamina in its wall, while small adjacent normal arteries have their internal elastic lamina darkly stained with elastin stain . Lack of elastin in the aneurysm allows systolic pressure to enlarge and thin the wall. (Right) Trichrome stain of the saccular aneurysm reveals the collagenous nature of the aneurysmal wall. Note the thin area of the wall that puts saccular aneurysms at risk of leaking and rupture to cause SAH .

Organ System Approach to Autopsy: Sudden and Unexpected Death

SUBARACHNOID HEMORRHAGE

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STROKE

This brain removed at autopsy shows a large intraparenchymal hemorrhage producing bulging and discoloration over much of the right hemisphere. This finding is readily apparent on external examination.

TERMINOLOGY Definitions

Infarction: Ischemic necrosis due to lack of oxygenated blood Lacunar infarct: Small (< 15 mm) cyst-like subcortical infarct due to small penetrating branch artery occlusion Hemorrhage: Extravascular accumulation of blood (may be consequence of infarction, especially embolic) Stroke: Cerebral damage caused by either infarction or hemorrhage

ETIOLOGY/PATHOGENESIS Atherosclerosis/Arteriosclerosis Contributing factors include age,

Hereditary/Metabolic

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)

Cerebral amyloid angiopathy Hematologic: Hyperviscosity (polycythemia), sickling, hypercoagulability

Vasculitis/Inflammatory

Autoimmune disease (dermatomyositis, lupus, rheumatoid arthritis)

Systemic vasculitis (ANCA-related diseases) Primary CNS vasculitis Neurosarcoidosis Acute hemorrhagic leukoencephalitis

Toxic/Iatrogenic

Embolic Infarction

Fungal (Aspergillus)

Vascular/Developmental

Aneurysms, arteriovenous malformation, Moyamoya

104

parenchymal hemorrhage

Drugs of abuse (cocaine, amphetamines,

Heart (mural thrombus): Atrial fibrillation, infarction, endocarditis Fat: Long bone trauma Plaque: Carotid artery atherosclerosis/plaque rupture

Venous (cavernous sinus) thrombosis with

hypercholesterolemia, diabetes, smoking, hypertension Carotid arteries and named arteries of the cerebrovascular tree affected Infarction hemorrhage Hemorrhagic infarction occurs in wedge-shaped vascular territory

Sources of emboli

-amyloid immunostaining in amyloid angiopathy shows accumulation in the media of cerebral blood vessels in the meninges and parenchyma. (Courtesy J. Chiaffarano, DO.)

disease (hereditary or acquired cerebral arterial constrictions), cavernoma Hypertensive intracranial hemorrhage Basal ganglia, cerebellum, or brainstem (intraparenchymal, no vascular territory pattern)

phencyclidine)

Overanticoagulation

Infections

Herpes simplex encephalitis Infection-related vasculitis (syphilis, HIV, Lyme, Whipple, Hepatitis B and C)

Tumors

Primary tumors (hemangioblastoma, glioblastoma) Metastatic (especially melanoma, renal cell carcinoma, choriocarcinoma)

Lymphomatoid granulomatosis

Trauma

Cortical contusion Infarction due to subarachnoid hemorrhage

Key Facts Terminology

Infarction: Ischemic necrosis due to lack of oxygen blood flow

Hemorrhage: Extravascular accumulation of blood (may be consequence of infarction, especially embolic)

Clinical Issues

10% of strokes are hemorrhagic at initial onset 30% of strokes (initially nonhemorrhagic) will undergo hemorrhagic transformation

Microscopic Pathology Acute infarction

Edema, red neurons, neuron "ghosts," neutrophils, vacular proliferation Subacute infarction

Macrophages, neuropil rarefaction (necrotic debris), astrocytic gliosis, calcification Old infarction Cystic change (without fibroblasts or collagen), rare macrophages, gliosis in surrounding tissue Vasculitis: Transmural inflammation fibrinoid necrosis AVM: Arteries, veins, and hybrid vessels with intervening gliotic brain tissue Cavernoma: Back-to-back thin-walled vessels Amyloid angiopathy: Amorphous eosinophilic deposits

Diagnostic Checklist

Distinguish focal ischemia (red neurons in infarct territory) from global anoxic injury (red neurons bilaterally in hippocampus, Purkinje cells)

CLINICAL ISSUES

Treatment

Epidemiology

Carotid endarterectomy Surgical drainage &/or placement of extraventricular drain Inferior vena cava filter, cardiac septal defect repair or occluder device Medical approaches Anticoagulation, aspirin, antiplatelet agents Calcium channel blockers for vasospasm in subarachnoid hemorrhage

Incidence

Race: Stroke more common in black patients (compared to white patients) Sex: Atherosclerosis-related infarction more common in men 10% of strokes are hemorrhagic at initial onset Commonly seen in hypertensive hemorrhage, amyloid angiopathy, tumors, vascular malformations, and drug reactions 30% of strokes (initially nonhemorrhagic) will undergo hemorrhagic transformation 24 hours to 2 weeks after infarction Risk factors: age, anticoagulation, larger infarction, and embolic cause Between ages 45-85, stroke incidence doubles each decade

Presentation

Pertinent history: Transient ischemic attacks, trauma, malignancy, cardiac arrhythmias, anticoagulant use, drug abuse, infection/fever, endocarditis Symptoms localize to area of brain involved Motor &/or sensory deficits: Pre/post central gyrus Speech or visual disturbance: Parieto-occipital Focal cognitive deficits or agnosias: Frontal Cranial nerve involvement Decreased level of consciousness Multiple small subcortical infarcts may present as dementia

Laboratory Tests

Electroencephalography (EEG) pattern may suggest herpes encephalitis

Hypercoagulability: Serum levels of protein C, protein S, antithrombin III, factor V Leyden, lupus anticoagulant PT (INR), PTT C-ANCA, p-ANCA, rheumatoid factor, ANA

Surgical approaches

Organ System Approach to Autopsy: Sudden and Unexpected Death

STROKE

IMAGE FINDINGS Ultrasonographic Findings

Duplex (Doppler): Internal carotid artery stenosis Echocardiography: Vegetations and septal defects (paradoxic embolism)

CT Findings

Acute hemorrhage: Hyperdense Early infarction: Edema (hypoattenuation, sulcal effacement) or hyperdensity in a vessel

Later infarction: Hypodense Lacunar infarcts: Small hypodensities in basal ganglia and subcortical white matter

MR Findings

Different MR sequences demonstrate different pathologies optimally

Gradient echo MR: Hemorrhage hypointense T2 and FLAIR sequences: Infarction hyperintense Diffusion MR: Very early infarction Perfusion MR: Surrounding reversible ischemia

Angiography

Vascular malformations, aneurysms Venography: Venous thrombosis Vasculitis: "Beading" of vessels, or tapered segmental narrowing

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Organ System Approach to Autopsy: Sudden and Unexpected Death

STROKE

MACROSCOPIC FEATURES External Examination Musculoskeletal

Old infarction: Atrophy of unilateral limb muscles, facial asymmetry, contractures Long-term immobilization decubitus ulcers Trauma: Examine body for bruises and fractures, scalp for hematomas, bruising around eyes or blood in ears indicating basal skull fracture Needle tracks, injection sites indicating intravenous drug use Facies of Down syndrome or cachexia associated with Alzheimer disease (increased risk of amyloid angiopathy)

Internal Examination

Examine heart, aorta, coronary and renal arteries, kidneys for evidence of atherosclerotic vascular disease Examine cardiac valves for vegetations

Gross Examination of Brain

Surface hemorrhages, uncal or tonsillar herniation, or sulcal effacement suggesting edema Cut sections Very early infarction: Blurring of gray-white junction and softening of tissue Acute infarction: More softening, edema, discoloration, possibly hemorrhagic transformation Old infarction: Cystic cavitation (lacune) Acute hemorrhage: Red-brown, mass forming Old hemorrhage: Cavitation with orange/yellow rim Atrophy (sulcal widening and gyral narrowing) Alzheimer disease, which can coexist with amyloid angiopathy

MICROSCOPIC PATHOLOGY Histologic Features Ischemic injury

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Hypoxic-ischemic or "red" neurons Shrunken, hypereosinophilic cytoplasm and dark, condensed pyknotic nuclei Prominent in hippocampus (neocortex), and cerebellum (Purkinje cells) Appear within 6-48 hours of ischemic injury White matter infarcts: Transected axons near infarct may be seen as axonal swelling Edema: Pericellular and perivascular vacuolation Infarction Acute Edema, red neurons, vascular endothelial swelling, neutrophils in 24-48 hours Subacute Macrophages, neuropil rarefaction, reactive astrocytes Old Cystic change (without fibroblasts or collagen), rare macrophages, gliosis in surrounding tissue Emboli

Thrombus, atheroma, air, fat, septic embolus (endocarditis), cardiac myxoma, foreign material Vasculitis: Transmural inflammation of vessel walls fibrinoid necrosis Composition of inflammatory infiltrate varies with etiology Malformations/tumors AVM: Arteries, veins, and arterialized veins with intervening gliotic brain tissue Cavernoma: Back-to-back thin-walled vessels Amyloid angiopathy: Amorphous eosinophilic deposits in media and adventitia of small and medium-sized arteries, arterioles

ANCILLARY TESTS Histochemistry

Congo Red Elastic Martius Scarlet Blue

Immunohistochemistry

HSV1 and HSV2 -amyloid (amyloid angiopathy) GFAP (gliosis)

DIAGNOSTIC CHECKLIST Clinically Relevant Pathologic Features

Examine carotid and cerebral arteries (atherosclerosis) Sample hemorrhage rim for tumors, AVM, amyloid angiopathy

Exclude cardiac septal defects, mural thrombi, vegetations

Pathologic Interpretation Pearls

Distinguish focal ischemia (red neurons in infarct territory) from global anoxic injury (red neurons bilaterally in hippocampus, Purkinje cells) Uncal herniation from any cause can compress ipsilateral posterior cerebral artery, infarcting hippocampus, thalamus, occipital lobe

REPORTING CRITERIA Location and Evolution of Infarct

Give vascular territory of infarction and age (acute, subacute, old)

Source of Hemorrhage

Give cause of parenchymal or subarachnoid hemorrhage and age (organization, hemosiderin within macrophages)

SELECTED REFERENCES 1. 2.

Fewel ME et al: Spontaneous intracerebral hemorrhage: a review. Neurosurg Focus. 15(4):E1, 2003 Garcia JH: The evolution of brain infarcts. A review. J Neuropathol Exp Neurol. 51(4):387-93, 1992

Gross and Microscopic Features (Left) This coronal section through a fixed brain shows old lacunar infarcts of the right putamen and globus pallidus . (Right) This H&E-stained section shows an old infarction with an area of cavitation traversed by small vessels, containing residual macrophages and surrounded by gliosis.

(Left) H&E section through old/chronic hemorrhagic infarct with loss of neuropil and gliosis surrounded by hemosiderin-laden macrophages. (Right) This axial section of cerebellum shows old infarction in the right hemisphere , characterized by atrophy, yellow discoloration, and shrinkage of the folia. The changes are apparent when compared to the opposite side .

Organ System Approach to Autopsy: Sudden and Unexpected Death

STROKE

(Left) This polarized light image of a Congo redstained section of autopsy brain demonstrates applegreen birefringence, confirming the presence of amyloid. Amyloid angiopathy is a common cause of cerebral hemorrhage in older adults. (Right) This H&Estained section of amyloid angiopathy shows vessels with eosinophilic deposits in the medial layer of arterioles with characteristic rigid round pipe shapes.

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Gross and Microscopic Features (Left) These cross sections through the occipital lobes of a fixed brain show the typical wedge-shaped or lobar hemorrhages of cerebral amyloid angiopathy. (Right) Red neurons with ischemic necrosis are seen on H&Estained sections. These neurons are shrunken, with hypereosinophilic cytoplasm and pyknotic nuclei.

(Left) This H&E/Luxol fast blue-stained section of brain adjacent to an area of acute infarction shows axonal swellings , indicating white matter tract disruption, and also shows pericellular vacuolation consistent with edema. (Right) This H&Estained image of subacute infarction shows ischemic neurons , edema with pericellular vacuolization, and no significant inflammatory response.

(Left) Gross image of frontal lobe shows vascular malformation that is likely cavernoma (back-to-back small vessels with hemosiderin staining of surrounding parenchyma). (Right) This trichrome stain of a cavernoma shows back-to-back thinwalled vessels without evidence of internal elastic lamina.

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Gross and Microscopic Images (Left) Coronal section through the brain shows embolic infarction (may be septic or thromboembolic) with focal lesions at the graywhite junction and in the white matter . (Right) This coronal section of brain with herpes encephalitis shows hemorrhagic necrosis of the right temporal lobe.

(Left) Gross image shows arteriovenous malformation and surrounding hemorrhage with a collection of vessels of varying sizes. Note the enlarged lateral ventricle and 3rd ventricle, likely from hemorrhage into the ventricles. (Right) This H&E-stained section of an arteriovenous malformation shows vessels with varying wall thickness with intervening gliotic brain tissue between vessels (i.e., not back-to-back).

Organ System Approach to Autopsy: Sudden and Unexpected Death

STROKE

(Left) H&E-stained section shows organized fibrin thrombi in small vessels, consistent with DIC or TTP. (Right) Coronal section of a fresh brain at autopsy shows hemorrhagic melanoma. Sulcal effacement and subfalcine herniation accompany edema of the right cerebral hemisphere.

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SECTION 2

Postoperative/PostInterventional Death

Iatrogenic Therapeutic Complications

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Cardiovascular Coronary Artery Bypass Grafting

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Coronary Artery Stenting

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Valve Replacement (Including Transcatheter)

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Ventricular Assist Devices

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Thoracic Aortic Aneurysm Repair

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Gastrointestinal and Hepatobiliary Pancreas Resection

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Gastrectomy and Esophagectomy

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Bariatric Surgery

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CNS Central Nervous System Tumors

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Cerebral Aneurysm and Vascular Malformation

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

THERAPEUTIC COMPLICATIONS

This patient who underwent a mitral valve repair with a pericardial valve could not be weaned off of bypass without the insertion of a circulatory assist device . Death was considered a therapeutic complication.

TERMINOLOGY Synonyms

Iatrogenic Injury, therapeutic misadventure

Semantics: "Misadventure" considered pejorative; "complication" favored

Definitions

Therapeutic complication: Injury or adverse event

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caused by medical management, not underlying disease May not be overtly evident at autopsy, and identification requires careful clinical pathological correlation Includes medication errors as well as interventional complications May not be ultimate cause of death but contributory e.g., patient who had anaphylactic reaction to antibiotic but survived and ultimately died from infection; patient who had small hemothorax after central line placement (treated) but died from underlying heart failure Clinically unsuspected diagnoses: Distinct from therapeutic complication, refers to autopsy diagnoses that were not identified premortem and may have impacted outcome Classification schema: Goldman criteria Class I: Major missed diagnosis with potential for adverse outcome that would have changed clinical management Class II: Major missed diagnosis without potential impact on survival that would not have changed clinical management Class III: Missed minor diagnosis related to terminal disease but not causing death Class IV: Other missed minor diagnosis

A therapeutic complication and major missed clinical diagnosis are demonstrated here in a large hematoma that surrounded a ventricular assist device generator and had been clinically diagnosed as an infection.

EXAMPLES OF THERAPEUTIC COMPLICATIONS Surgical: Infectious, Medication, Anesthesia, Technical, Nontechnical, Thromboembolic, Transfusion-Related Infectious complications

Common: Local wound infection, postoperative pneumonia, line and urinary tract infection Can progress to systemic infection and shock Host and operative factors important determinants: Underlying immunosuppression, bowel surgery Medication complication Similar to nonsurgical complication: Any adverse reaction to medication given as part of operative intervention Adverse reaction usually anaphylactic Pulmonary congestion and edema, sometimes laryngeal and upper airway edema, mucus plugging and hyperinflation of lungs, and petechial hemorrhages (asphyxia/anoxia) Anesthesia complication Adverse reaction to anesthetic agents, ventilatory issues, malignant hyperthermia (MH) If MH diagnosis, consider molecular testing on pre- or early postmortem blood; final report should indicate familial nature (most autosomal dominant) of disease and risk to next of kin Technical complication Complication directly related to operation: Wound dehiscence, anastomotic leaking (e.g., bowel surgery), postoperative bleeding Nontechnical complication Epiphenomenon of operative intervention Ileus, postoperative atelectasis Uncommon direct cause of death Thromboembolic

Venous thromboembolism in postoperative period Patient factors: Preoperative thrombophilia, obesity, underlying malignancy, hip fracture, spinal cord injury, major trauma Operative factors: Major operation (thoracic or abdominal surgery with general anesthesia lasting > 30 minutes), hip or knee replacement Transfusion-related Any operative intervention-related transfusion complication Transfusion-associated circulatory overload: Pulmonary edema related to osmotic effects of transfused red blood cells leading to increased intravascular volume (2nd most common cause of transfusion related death) Acute hemolytic transfusion reaction: Usually due to recipient antibodies to RBC antigens; ABO most common but may relate to other antigens; intravascular hemolysis hemoglobinuria, acute renal failure, DIC, and occasionally death Transfusion-related acute lung injury (TRALI): Uncommon reaction due to presence of anti HLA or anti leukocyte antibodies in donor plasma leukocyte degranulation in lung and diffuse alveolar damage If transfusion-related complication is noted at autopsy, consult with transfusion medicine specialists and consider collecting plasma and blood from decedent; hold any premortem blood in laboratory

Technical: Complication of technical aspects of invasive but nonoperative intervention e.g., pancreatitis or bleeding following endoscopic retrograde cholangiopancreatography (ERCP); coronary artery dissection during coronary angiogram Nontechnical: Complication following invasive but nonoperative intervention e.g., dysrhythmia or cholesterol embolization syndrome following coronary angiography Thromboembolic Venous thromboembolism in hospital or other health care (nursing home) setting Risk factors: Underlying thrombophilic (protein C or S, factor V Leiden mutation), obesity, immobility, malignancy, hormonal therapy Transfusion-related Same complications as transfusion in operative setting

CLINICALLY UNSUSPECTED DIAGNOSES Final Autopsy Report

All major and minor clinically unsuspected diagnoses should be documented

Major clinically unsuspected diagnoses should be flagged for QA review

Minor clinically unsuspected diagnosed should also be documented and are also important as they may have impact for next of kin e.g., class IV missed diagnosis of unsuspected malignancy like medullary carcinoma of thyroid may have familial implication

Nonsurgical: Infectious, Medication, Procedure-Related (Technical or Nontechnical), Thromboembolic, Transfusion-Related

Infectious complication: Nosocomial (hospitalacquired) infections (HAI): Infections that are associated with hospital or health care (health careassociated infection) An important cause of morbidity and mortality in hospitalized patients and patients in other health care settings (nursing homes) Most common nonsurgical HAI: Central line and urinary catheter-associated infection, Clostridium difficile infection, and methicillin-resistant Staphylococcus aureus Other important HAI: Ventilator-associated pneumonia, hospital-acquired pneumonia, and vancomycin-resistant enterococcus Autopsy identification of clinically undiagnosed HAI should be reported to hospital infection control or infectious disease team Medication: Any adverse reaction to administered medication Can include interactions including over the counter medications and herbal medication Anticoagulation therapy-related injury: Bleeding related to anticoagulation therapy Gastrointestinal, retroperitoneal, cerebral Procedure-related technical and nontechnical

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

THERAPEUTIC COMPLICATIONS

SELECTED REFERENCES 1. 2.

4. 5. 6. 7.

Langford NJ: Therapeutic misadventure. Med Sci Law. 50(4):179-82, 2010 Grzybicki DM et al. Anatomic pathology and patient safety: it’s not an error: it’s a diagnostic misadventure! Am J Clin Pathol. 129(1):167-8; author reply 169, 2008 Lau G: Perioperative deaths: a further comparative review of coroner’s autopsies with particular reference to the occurrence of fatal iatrogenic injury. Ann Acad Med Singapore. 29(4):486-97, 2000 Pumphrey RS et al: Postmortem findings after fatal anaphylactic reactions. J Clin Pathol. 53(4):273-6, 2000 Goldman L et al: The value of the autopsy in three medical eras. N Engl J Med. 308(17):1000-5, 1983 Utting JE et al: Human misadventure in anaesthesia. Can Anaesth Soc J. 26(6):472-8, 1979 Therapeutic misadventure. Br Med J. 1(5594):724, 1968

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THERAPEUTIC COMPLICATIONS

Gross and Microscopic Features (Left) Clostridium difficile enterocolitis is an important hospital-acquired infection. It has a pseudomembranous appearance with yellow nodules overlying the mucosa. (From DP: Gastrointestinal.) (Right) The pseudomembranes of Clostridium difficile enterocolitis are composed of mushrooms of mucus, acute inflammatory cells, and degenerated superficial epithelial cells. The base of the crypts is intact. (From DP: Gastrointestinal.)

(Left) Cirrhosis is a commonly missed clinical diagnosis and also is an important cause of medical complication, particularly Tylenol use in patients with alcoholism and cirrhosis. (Right) This mass of thromboemboli was found in the bifurcation of the pulmonary artery in a patient who was recently postoperative. Major surgery (thoracic or abdominal surgery with general anesthesia > 30 minutes) and hip and knee replacement surgery has a high risk of pulmonary thromboembolism.

(Left) This is an example of a patient who expired due to ascending aortic dissection with rupture and hemothorax. The patient had undergone operative repair (sutures ) and died on the table. This death would still be classified as a natural death, not therapeutic complication, due to the emergent nature of the situation and lethal nature of aortic dissection. (Right) Rupture of an aortic aneurysm after stent graft repair is a known therapeutic complication.

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Gross and Microscopic Features (Left) Even a minor clinically unsuspected diagnosis like a thyroid carcinoma that has features of medullary carcinoma may have potential impact for the surviving next of kin. This thyroid demonstrates a large medullary carcinoma that has a gray-white appearance and was firm. (From DP: Endocrine.) (Right) The histologic features of medullary thyroid cancer are seen here with a cellular tumor with a stroma rich in amyloid . (From DP: Endocrine.)

(Left) This case demonstrates ischemic necrosis of the transverse colon . This would be classified as a major missed diagnosis with potential for adverse outcome that would have changed clinical management. (Right) Ischemic colitis with a pseudomembrane is noted here. There is epithelial necrosis and interstitial hemorrhage and homogeneous pink appearance to lamina propria . (From DP: Gastrointestinal.)

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

THERAPEUTIC COMPLICATIONS

(Left) Widely metastatic malignancy in a young boy who expired within hours of admission is not a clinically unsuspected diagnosis. (Right) The quick death was due to severe pulmonary hypertension caused by tumor metastasis with to the lungs associated marked intimal hyperplasia of pulmonary arteries . Death was due to natural causes without clinically unsuspected diagnosis.

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CORONARY ARTERY BYPASS GRAFTING

Anterior view of autopsied heart shows aortocoronary saphenous vein grafts to right coronary , left anterior descending (LAD) , and obtuse marginal targets. An additional posterior descending graft has been cut.

TERMINOLOGY

Complications

Abbreviations

"Kinking" or obstruction of graft body Acute thrombosis (often due to hypercoagulability) Late Fibrointimal proliferation and atheromatous plaques

Coronary artery bypass grafting (CABG)

CLINICAL ISSUES

IMAGE FINDINGS

artery disease, CABG has largely been replaced by percutaneous endovascular procedures (angioplasty and stenting). CABG is still performed in setting of Patients with coronary disease and valve disease or other need for open heart surgery Left main coronary disease (given the consequences of endovascular complication in this location) Certain patients with severe multifocal disease Patient outcomes post stenting are not better than post CABG, but stenting is obviously less invasive

Specimen Radiographic Findings

Patient History Review

Operative reports or coronary angiograms relevant to grafting targets and conduits are key to success in postCABG heart evaluation Dense pericardial adhesions may make it difficult to identify some grafts Left internal mammary artery (LIMA) grafts are easily obliterated upon removal of sternal chest plate Old thrombosed graft conduits may become threadlike and difficult to identify Mention of triple, quadruple, etc., bypass refers to number of target vessel anastomoses

Expected Graft Conduit Longevity

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Early

Clinical Overview

Once the primary intervention for coronary

3D reconstruction CT angiogram shows bypass grafts to the posterior descending and obtuse marginal coronary branches. (From DI: Cardiovascular.)

Internal mammary artery graft: 90% patency at 10 years

Saphenous vein graft (SVG): 20-30% patency at 10 years

Identify course of graft (clips along LIMA and SVG from graft harvesting): "Connect the dots"

Delineate calcific plaque in native vessels and grafts Reveal any metallic stents

MACROSCOPIC FEATURES General Features

Common sources of graft conduits

Veins: Saphenous, gastroepiploic/inferior epigastric Arteries: Internal mammary, radial Scar patterns on external (skin) exam provide clues Endoscopic vein harvesting may leave only subtle scars Common target vessels Left anterior descending (LAD) Ramus intermedius branch: Small branch arising at bifurcation of LAD and left circumflex (LCX) (trifurcation instead of bifurcation) Diagonal branches: Primary branches of LAD serving anterior left ventricle LIMA grafts almost exclusively to LAD due to anatomic constraints and adjacency LCX Obtuse marginal branches: Primary branches (or sometimes terminal course of LCX) serving lateral left ventricle Right coronary artery (RCA)

Key Facts Clinical Issues

LIMA grafts are easily obliterated upon removal of

to grafting targets and conduits are key to success in post-CABG heart evaluation Internal mammary artery graft: 90% patency at 10 years Saphenous vein graft: 20-30% patency at 10 years Once the primary intervention for coronary artery disease, CABG has largely been replaced by percutaneous endovascular procedures (angioplasty and stenting) Patient outcomes post stenting are not better than post CABG, but stenting is obviously less invasive Dense pericardial adhesions may make it difficult to identify some grafts

Macroscopic Pathology

Operative reports or coronary angiograms relevant

Posterior descending: Terminal course of RCA serving posterior/inferior left ventricle Posterior descending may be terminal course of LCX in ~ 10% of patients (left dominant circulation) Posterolateral branch: Branch extending beyond posterior descending artery serving posterolateral left ventricle Sequential grafts Lengthy segments of conduit may be used to supply > 1 target vessel anastomosis "T" (perpendicular side-to-side) or "Y" (juxtaposed end-to-side) graft configurations Each target vessel should be labeled and evaluated individually

Sections to Be Submitted

Proximal native coronary arteries

All vessels should be examined per routine to document need for CABG and apparent collateral (retrograde) flow For each bypass target vessel, document Graft body: Serially sectioned with areas of plaque, thrombus, or other stenosis selected for microscopy Distal anastomosis: Serial cross sectioning along axis of either native vessel or graft body; submitted entirely Distal native vessel run-off: Serial cross sectioning to evaluate potential for flow beyond target site Proximal anastomosis for SVG can often be inspected grossly for patency and does not routinely need to be submitted Decalcification often necessary prior to sectioning &/ or before tissue cassette processing

MICROSCOPIC PATHOLOGY Histologic Features

Evaluate for plaque and thrombosis, recanalization % stenosis, recent/organized, shallow/occlusive

sternal chest plate

For each bypass target vessel, document

Graft body: Serially sectioned with areas of plaque, thrombus, or other stenosis selected for microscopy Distal anastomosis: Serial cross sectioning along axis of either native vessel or graft body Distal native vessel run-off: Serial cross sectioning to evaluate potential for flow beyond target site Common sources of graft conduits Veins: Saphenous, gastroepiploic/inferior epigastric Arteries: Internal mammary, radial Labeling and nomenclature Convention: Label graft according to target vessel and graft body type

Internal mammary artery graft: Characteristic multilaminar elastic artery wall

SVG: Single elastic layer, adventitial smooth muscle bundles Arterialization Distinct internal elastic lamina, intimal fibroplasia, and plaque Anastomosis Usually elongated, "figure 8," or otherwise distorted lumen contour with part of vessel circumference made of native artery and part from graft body Paired suture holes serve as useful landmarks for anastomosis ("snake eyes")

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CORONARY ARTERY BYPASS GRAFTING

REPORTING CONSIDERATIONS Key Elements to Report

Report % stenosis of native target vessel, graft body, anastomosis, and distal vessel

Labeling and Nomenclature

Convention: Label graft according to target vessel and graft body type

Examples

LAD-D1-LIMA: Left internal mammary graft to 1st diagonal branch of LAD LCX-OM2-SVG: Saphenous vein graft to 2nd obtuse marginal branch of LCX RCA-PL-SVG: Saphenous vein graft to posterolateral branch of RCA

SELECTED REFERENCES 1. 2.

3. 4.

Lau GT et al: Cardiac saphenous vein bypass graft disease. Semin Vasc Med. 4(2):153-9, 2004 Schoen FJ: Ischemic heart disease: aortocoronary bypass grafting. In Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlation and Basic Principles. W. B. Philadelphia: Saunders. 82-92, 1989 Titus JL: The heart after surgery for ischemic heart disease. Am J Cardiovasc Pathol. 1(3):339-51, 1988 Bulkley BH et al: Pathology of coronary artery bypass graft surgery. Arch Pathol Lab Med. 102(6):273-80, 1978

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CORONARY ARTERY BYPASS GRAFTING

Gross Features (Left) This heart has had multiple cardiac procedures. External pacing wires and a left ventricular assist device are seen. inflow cannula There are also bypass grafts to the posterior descending and posterolateral coronary branches. (Right) This obviously dilated heart shows a sequential "T" graft with side-to-side anastomosis to the LAD (graft body mostly removed) and then continuing around to the posterolateral branch (end-toside) .

(Left) This bypass graft has been dissected free from the heart. The proximal portion contains the ostium and a portion of the aorta. The distal portion includes ventricular muscle surrounding the anastomotic site. (Right) The distal portion of this saphenous vein graft includes a portion of the graft body . A generous tissue block is taken around the anastomotic site to avoid disrupting delicate structures . The entire anastomosis area should be sectioned and submitted.

(Left) Photo shows 2 separate graft anastomoses. The site can be identified by a figure 8. The native shaped contour vessel is also seen in cross section. (Right) This autopsy heart specimen (shown after short-axis sectioning of the ventricles) shows 2 coronary artery bypass grafts. There is a LIMA graft to the proximal circumflex as well as a saphenous vein graft to the mid LAD .

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Microscopic Features (Left) Elastic stain section shows a muscular (radial) artery graft body characterized by distinct external and internal elastic layers. The target native vessel shows significant plaque with old plaque hemorrhage. The site is patent, without fibrous intimal ingrowth. (Right) Paraffin section shows a LIMA-to-LAD anastomosis. The LIMA can be identified by its characteristic multilaminar elastic wall . Paired suture holes are present at the union site.

(Left) This photomicrograph of a bypass anastomosis shows the native coronary artery with obstructive plaque forming the bottom half of the wall and the vein graft forming the top half. This graft acutely thrombosed . (Right) This elastic stain of the same anastomotic site illustrates how the native coronary artery can be differentiated from the vein graft by its internal elastic lamina . Suture holes are also a landmark for the anastomosis .

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CORONARY ARTERY BYPASS GRAFTING

(Left) This section of saphenous vein graft body shows old thrombotic occlusion . The vein graft has undergone "arterialization" with formation of a distinct internal elastic layer . Adventitial smooth muscle bundles confirm the venous nature of the vessel. (Right) This graft anastomosis site shows minor native vessel disease but severe calcific plaque involving the body and anastomotic site.

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CORONARY ARTERY STENTING

Graphic shows a deployed stent within an atherosclerotic vessel , balloon inflation with dilatation of the stenotic segment , and retrieval of catheter after stent placement .

TERMINOLOGY Stents are prosthetic intraluminal tubular metal scaffold devices designed to maintain lumen patency in setting of underlying intrinsic or extrinsic coronary artery disease Can be deployed by inflation of balloon-tipped endovascular catheter Balloon inflation disrupts vessel wall plaque and expands lumen Stent holds lumen open Different metals used Surgical-grade stainless steel Metal alloys (cobalt-chromium, platinumchromium, nickel-titanium [nitinol]) May be "bare metal" or coated with drug-eluting polymers (CYPHER [sirolimus], TAXUS [paclitaxel], XIENCE V [everolimus]) designed to inhibit neointimal growth

Indications

Primary therapy for coronary atherosclerosis

Revascularization therapy in acute myocardial infarction Bailout procedure for abrupt or threatened artery closure due to arterial dissection or following angioplasty Also attempted in some cases of cardiac allograft vasculopathy

Complications

Reocclusion/restenosis of stented coronary artery

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Late restenosis results from concentric neointimal growth or thrombosis

Definitions

CLINICAL IMPLICATIONS

Photograph of multiple stents in a coronary artery dissected from an explanted heart shows exposed stent struts and struts enveloped in neointimal tissue . This method of stent examination is not advised.

segments (in-stent restenosis) occurs in 5-30% of cases Early restenosis usually results from acute thrombosis

MACROSCOPIC FINDINGS External Examination

If recent intervention, inspect percutaneous cannulation site (groin, wrist, or neck) for hematoma or vascular complication Other scars indicating cardiac interventions Median sternotomy Other thoracotomy Saphenous vein or radial artery harvesting

Internal Examination Heart

Identify and carefully dissect internal mammary graft conduits, if present Coronary arteries can be examined in situ or dissected free from heart Care should be taken not to crush or excessively bend stented artery segments (artifactual fracturing) Specimen radiograph of entire heart vs. dissected coronaries

Organ Examination

Specimen radiographs should be used to delineate stents within cardiovascular specimens Radiographs are important to assess stent expansion and determine whether stent was abnormally compressed during deployment Total stented length and curvature should be documented since these correlate with risk of restenosis Any apparent stent strut fractures should also be noted Evaluation for restenosis is made difficult by metallic stents that cannot be cut by conventional methods (scissors, scalpels, or conventional microtome blades)

Disruption of normal histoarchitecture (especially stent-tissue interface) will occur if conventional methods are attempted Avoid attempts to cut through stents with scissors or scalpel Trim stented vessel by cutting proximal and distal to stent Fix stented segment in formalin prior to special handling

MICROSCOPIC FINDINGS Methods of Stent Sectioning for Microscopy Plastic resin embedding and diamond or tungsten

carbide blade microtomy Stented vessel tissue fixed and embedded in rigid methacrylate resin (as used in transmission electron microscopy) microtomy Cut using conventional microtome equipped with special blade hard enough to cut metal stents Diamond saw microtome Stented vessel tissue fixed and embedded in plastic and cut with high-speed diamond saw with precision movement capable of cutting ~ 10 m sections Used in undecalcified bone mineral density samples Sawing and grinding Stented vessel tissue fixed and embedded in plastic then subject to 2-stage process of sawing into ~ 100 m sections that are mounted with adhesive to glass slide Slide is then placed in sanding/grinding device that progressively erodes thick section down to < 10 m thickness Reverse electroplating Prior to embedding, fixed stented vessel is placed in acid-salt solution, and electrodes are connected to stent metal Current is applied in such a way that stent metal dissolves by electrolysis Vessel can then be sectioned with scalpel and submitted for routine paraffin sectioning

Fibrin and platelet aggregation is seen commonly around struts during 1st week Elastic lamina disruption, a consequence of balloon inflation, is common and does not indicate vasculitis Late complications Smooth muscle-rich neointimal proliferation may significantly occlude lumen Late stent thrombosis is usually associated with malapposed struts or delayed incorporation Multinucleated giant cells around struts are more common after 30 days

SELECTED REFERENCES 1.

3. 4.

Stone JR et al: Recommendations for processing cardiovascular surgical pathology specimens: a consensus statement from the Standards and Definitions Committee of the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology. Cardiovasc Pathol. 21(1):2-16, 2012 Nakazawa G et al: The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol. 57(11):1314-22, 2011 Bradshaw SH et al: A practical method to rapidly dissolve metallic stents. Cardiovasc Pathol. 18(3):127-33, 2009 Nakazawa G et al: A review of current devices and a look at new technology: drug-eluting stents. Expert Rev Med Devices. 6(1):33-42, 2009 Lscher TF et al: Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation. 115(8):1051-8, 2007 Rippstein P et al: Comparison of processing and sectioning methodologies for arteries containing metallic stents. J Histochem Cytochem. 54(6):673-81, 2006 Farb A et al: Morphological predictors of restenosis after coronary stenting in humans. Circulation. 105(25):2974-80, 2002

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CORONARY ARTERY STENTING

Histologic Features

Stented artery assessments should focus on both native vessel disease and any neointimal growth within stent Estimated cross-sectional area stenosis as well as plaque composition (fibrous, calcific, smooth muscle, lipid, necrosis, etc.) should be reported Artery sections immediately distal and proximal to stent should also be examined and reported Early complications Rupture of thin-cap atheromas induced by balloon inflation can lead to atherothrombosis or atheroemboli Lipid core penetration by struts is associated with increased acute/chronic inflammation and neointimal growth Malapposition of struts relative to vessel wall

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CORONARY ARTERY STENTING

Microscopic Features (Left) Plastic-embedded cross section of a stented coronary artery from an experimental model (without atherosclerosis) demonstrates proper apposition of stent struts to the vessel wall, causing some indentation and polygonal distortion of the circular lumen. (Right) Elastic-stained section of a stented coronary artery from an experimental model highlights a small dissection in the vessel resulting from balloon inflation during stent deployment. This is a recognized acute complication of the procedure.

(Left) Plastic-embedded cross section of a previously atherosclerotic plaque coronary artery is shown. There has been little to no neointimal formation, suggesting that the stent was placed very recently. The stent struts are well apposed to the wall. (Right) Elastic-stained plastic section of a stented coronary artery highlights the internal elastic lamina and intimal localization of atherosclerosis and the absence of neointima formation.

(Left) Elastic-stained plastic section of a stented coronary artery shows a significant native plaque , which obstructs > 75% of the original lumen, and in-stent restenosis caused by concentric neointimal ingrowth further restricting the lumen . (Right) Movat-stained plastic section shows a stent within a stent. There is a native plaque , a neointimal stenosis of the original (outer) stent , and a 2nd inner stent that was placed later, also showing significant stenosis.

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Microscopic Features and Ancillary Techniques (Left) Plastic-embedded coronary artery section shows 2 stent struts marking the original stented lumen boundary and substantial smooth musclerich neointimal ingrowth extending to the residual lumen at the top. (Right) Plastic section of stented coronary artery shows neointimal growth with neovascularization and inflammation surrounding the strut.

(Left) Higher magnification of the peri-strut neointimal tissue of a stented coronary artery highlights wisps of fibrin , sparse mononuclear cells, and a giant cell foreign body reaction . (Right) Paraffin section of a stented coronary artery after reverse electroplating to remove the metallic struts shows empty "holes" . Atherothrombosis , which had resulted from rupture of a thin-cap soft-core plaque during stent deployment, occludes the lumen.

(Left) This specimen radiograph of coronary arteries dissected free from the heart at autopsy helps facilitate further sectioning of the vessels and appropriate processing of stents . They also allow for identification of possible stent strut fractures. (Right) Photograph shows an apparatus for dissolving metallic stents from coronary artery specimens using reverse electroplating. Current is applied to the stent in an artery submerged in acidsalt solution after formalin fixation.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CORONARY ARTERY STENTING

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VALVE REPLACEMENT (INCLUDING TRANSCATHETER)

Cusp degeneration is a common cause of failure of bioprosthetic valves. Note nodular calcified deposits on the cusps of this bovine pericardial bioprosthesis, which resulted in valve stenosis.

TERMINOLOGY Abbreviations

Prosthetic valve (infective) endocarditis (PVE) Transcatheter aortic valve replacement (TAVR)

Major Types of Prosthetic Valves Mechanical

Ball-in-cage Tilting disc Bileaflet Bioprosthetic Porcine Bovine pericardial Cadaveric homograft Catheter-deployed bioprosthetic Edwards SAPIEN Medtronic CoreValve Medtronic Melody Others Other devices MitraClip (for percutaneous mitral valve repair)

Hemodynamic Categories of Failure Prosthetic valve stenosis Prosthetic valve regurgitation

CLINICAL ISSUES Clinical Overview

Selection of type of valve prosthesis driven by

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combination of patient factors and inherent advantages and disadvantages of each prosthesis Type of prosthesis will determine which complications might be seen during autopsy Mechanical prosthetic valves Advantages: Excellent durability (most remain functional for 20-30 years)

Infective endocarditis may involve prosthetic valves of any type. Here, vegetations have formed on a bileaflet mechanical valve, restricting leaflet mobility and causing severe stenosis.

Disadvantages: Require lifelong anticoagulation (risk of hemorrhage, teratogenicity in women of childbearing age), hemolytic anemia from mechanical trauma to RBCs Bioprosthetic valves Advantages: No anticoagulation required Disadvantages: Structural deterioration common (30-35% fail within 10-15 years) Catheter-deployed bioprosthetic valves Advantages: Less invasive (used for patients with high surgical risk), may be used when surgery is technically challenging or impossible; valve-in-valve procedures possible Disadvantages: Higher risk of stroke, longterm durability unknown, numerous unique complications as outlined below

Patient History Review

Clinical, operative, and echocardiography reports may delineate complications, anatomy, and hemodynamic abnormalities Review thereof can guide postmortem evaluation of prosthetic valve

Etiology of Prosthetic Valve Failure Thrombosis

More common with mechanical valves (inadequate anticoagulation) May cause stenosis &/or regurgitation May be complicated by embolism and downstream infarcts Structural deterioration Primarily involves bioprosthetic valves Cusp calcification usually causes stenosis Cusp tear causes regurgitation Usually tear occurs at commissure Results in cusp prolapse Paravalvular leak May occur with any type of prosthetic valve Results in regurgitation

Key Facts Clinical Issues

Type of prosthesis will determine which complications may be seen at autopsy

Mechanical: Very durable, but requires anticoagulation

Bioprosthetic: No anticoagulation, but structural deterioration common

Catheter-deployed: Less invasive, but numerous unique complications

Failure may cause stenosis &/or regurgitation Failure may affect heart, lungs, and other organs

Macroscopic Pathology

Causes of prosthetic valve failure: Thrombosis (esp. mechanical valves) Structural deterioration (esp. bioprosthetic valves) Paravalvular leak (all valves)

Pannus formation (all valves) Infective endocarditis (all valves) Incomplete expansion (catheter-deployed only) Suboptimal seating (catheter-deployed only) Other complications: Hemorrhage, embolism, infarcts, hemolytic anemia, etc.

Autopsy performance considerations Submit vegetations for microbiologic cultures Examine prosthetic valves from both sides Examine for perivalvular leaks, annular abscesses Obtain radiographs to evaluate cusp calcification, integrity of metallic components (e.g. struts)

Photograph abnormalities Evaluate for secondary cardiac/pulmonary disease Submit vegetations, perforations, abscesses, thrombi, and adherent tissues for microscopy

Pannus formation

Proper function requires alignment at level of anatomic annulus Improperly seated valves become loose and embolize distally Embolization of calcified debris from native cusps Dislodged during balloon expansion prior to valve deployment May cause strokes or infarcts in downstream organs Inverted orientation Valve deployed via transfemoral or transapical approach; must be properly oriented in catheter sheath to prevent inverted (backward) deployment Rare, but may be fatal Annular rupture Rare, but may be fatal; due to aggressive balloon predilatation Coronary ostial obstruction with myocardial infarction Rare; due to device itself or calcified debris from native aortic valve Complications specific to transapical approach Hemopericardium with cardiac tamponade Damage to mitral valve Left ventricular pseudoaneurysm formation Left ventricular arrhythmias Complications specific to transfemoral approach Aortofemoral injury/rupture Distal embolization of dislodged femoral, iliac, or aortic atherosclerotic plaque

Complications Specific to CatheterDeployed Valves

Other Complications

May occur with any type of prosthetic valve Annular fibrous ingrowth causes stenosis Infective endocarditis May occur with any type of prosthetic valve Causes regurgitation if valve structures are destroyed (e.g., perforations, cusp tears) or if surrounding native tissue is involved (with valve dehiscence) Causes stenosis if vegetations are large Infectious agents Staphylococcus epidermidis Staphylococcus aureus Streptococci Gram-negative bacilli Fungi Bioprosthetic infective endocarditis May involve cusps &/or sewing ring Sometimes complicated by annular abscess Mechanical prosthetic infective endocarditis Vegetations involve sewing ring Usually complicated by annular abscess Annular abscess May burrow, perforate, &/or cause valve dehiscence May extend to involve other valves High operative mortality rate Septic embolism May cause sterile or infected infarcts in downstream sites

Incomplete expansion

Proper leaflet coaptation requires full expansion to predesigned functional circumference Incomplete expansion may cause "tenting" of cusps and fixed regurgitation Overexpansion rarely seen given usual calcification and sclerosis of aortic annulus in aortic stenosis Suboptimal seating and attachment failure

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

VALVE REPLACEMENT (INCLUDING TRANSCATHETER)

Hemorrhage

Primarily with mechanical valves (due to anticoagulation) Embolism and infarcts Due to thrombosis or infective endocarditis Teratogenic effects Primarily with mechanical valves (due to warfarin) Hemolytic anemia Primarily with mechanical valves (due to mechanical trauma to red blood cells)

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VALVE REPLACEMENT (INCLUDING TRANSCATHETER)

MACROSCOPIC FEATURES

Valuable for medicolegal and educational purposes

At minimum, submit the following abnormalities for microscopy Vegetations, cusp perforations, other features suggestive of infection Annular abscesses Thrombi (to evaluate for infection) Any other tissue adherent to device

External Examination

If recent surgical intervention, inspect incision site for signs of infection (purulence, necrosis, dehiscence)

If recent transcatheter intervention, inspect

percutaneous cannulation site (groin, small left thoracotomy) for hematoma or vascular complication Other scars indicating previous cardiac interventions Median sternotomy Other thoracotomy Saphenous vein or radial artery harvesting

Internal Examination Brain and other viscera

Evaluate for infarcts due to embolization of valve thrombus or vegetations Lungs Evaluate for edema or other evidence of congestive heart failure due to failed valve prosthesis Body cavities Evaluate for evidence of procedure complications (e.g., hemopericardium, hemothorax)

Organ Examination Heart

Evaluate for disease of prosthetic valve Carefully remove great vessels &/or atria to expose valves ("base of heart" dissection method) If vegetations or annular abscesses are present, obtain material in sterile fashion for microbiologic cultures Examine prosthetic valves from both sides (inflow and outflow) Examine perivalvular tissues for abnormalities (e.g., perivalvular leaks, annular abscesses) Evaluate for evidence of valvular heart disease Record heart weight and standard measurements: LV, RV, septal wall thicknesses; LV internal shortaxis chamber diameter, RV internal short-axis chamber dimensions, annular circumferences of native valves Cardiac disease may be caused by native valve disease, prosthetic valve abnormalities, or both Examples of secondary cardiac effects of common valve diseases Aortic stenosis: LV pressure hypertrophy without LV dilatation; LA dilatation; RV/RA dilatation Aortic regurgitation: LV pressure and volume hypertrophy with massive 4-chamber dilatation Mitral stenosis: Normal LV, massive LA dilatation, RV/RA dilatation Mitral regurgitation: LV pressure and volume hypertrophy with 4-chamber dilatation Evaluate for other coexisting cardiovascular abnormalities Specimen radiography Useful to determine extent of cusp calcification Useful to evaluate for strut fractures and incomplete expansion of catheter-deployed valves Photograph abnormalities whenever possible

MICROSCOPIC PATHOLOGY Histologic Features Infective endocarditis

Abundant thrombotic material with destruction of prosthetic valve tissue, necrosis Dense neutrophilic, lymphoplasmacytic, or granulomatous inflammation Microorganisms may or may not be visualized Stains for microorganisms (e.g., Gram, GMS) can help, but negative result does not rule out infection Thrombi Recent thrombi show laminated appearance, with alternating layers of RBCs/WBCs and platelets/fibrin Older thrombi show organization with capillary proliferation Microorganisms and dense neutrophilic inflammation are absent

SELECTED REFERENCES 1.

Bourantas CV et al: Evolution of transcatheter aortic valve replacement. Circ Res. 114(6):1037-51, 2014 2. Lardizabal JA et al: The transaortic approach for transcatheter aortic valve replacement: initial clinical experience in the United States. J Am Coll Cardiol. 61(23):2341-5, 2013 3. Webb JG et al: Current status of transcatheter aortic valve replacement. J Am Coll Cardiol. 60(6):483-92, 2012 4. Lee JH et al: Prosthetic valve endocarditis: clinicopathological correlates in 122 surgical specimens from 116 patients (1985-2004). Cardiovasc Pathol. 20(1):26-35, 2011 5. Pibarot P et al: Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation. 119(7):1034-48, 2009 6. Siddiqui RF et al: Bioprosthetic heart valves: modes of failure. Histopathology. 55(2):135-44, 2009 7. Butany J et al: Analysis of prosthetic cardiac devices: a guide for the practising pathologist. J Clin Pathol. 58(2):113-24, 2005 8. Kent PD et al: Temporal changes in the surgical pathology of prosthetic aortic valves: a study of 157 cases spanning 26 years (1970-1995). Cardiovasc Pathol. 7(1):9-23, 1998 9. Milano A et al: Valve-related complications in elderly patients with biological and mechanical aortic valves. Ann Thorac Surg. 66(6 Suppl):S82-7, 1998 10. Cohn LH et al: Fifteen-year experience with 1678 Hancock porcine bioprosthetic heart valve replacements. Ann Surg. 210(4):435-42; discussion 442-3, 1989

Gross Findings (Left) Visualization of prosthetic valves is facilitated by the "base of heart" dissection method, whereby the atria are removed, revealing all four valves. Note a bileaflet mechanical prosthetic valve in the aortic position, as well as native tricuspid , mitral , and pulmonary valves. (Right) Fibrocalcific degeneration of all 3 prosthetic cusps and formation of pannus on the surface of one cusp resulted in stenosis of this bioprosthetic aortic valve.

(Left) Although more common on mechanical valves, thrombus may also form on the cusps of bioprosthetic valves, causing significant stenosis and potentially resulting in embolism and infarcts downstream. (Right) Structural degeneration is an important cause of failure of bioprosthetic valves. Here, significant fibrotic retraction of 2 cusps has resulted in torrential regurgitation of this porcine bioprosthetic valve. Also note focal pannus formation adjacent to one cusp.

(Left) Structural degeneration of bioprosthetic valves may also result in cusp tears, which usually form at commissures where mechanical strain and wear on the prosthetic cusp are greatest. Here, a large cusp tear has formed on this porcine bioprosthetic valve, resulting in severe regurgitation. (Right) On the reverse (inflow) side of this same valve, the extent of cusp tearing is more evident. The tear involves nearly the entire annular attachment of the involved cusp.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

VALVE REPLACEMENT (INCLUDING TRANSCATHETER)

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VALVE REPLACEMENT (INCLUDING TRANSCATHETER)

Infection: Gross and Microscopic Features (Left) Dehiscence is an important cause of prosthetic valve failure. Here, dehiscence of a cadaveric valved aortic homograft has resulted in formation of a perivalvular fibrotic cavity . (Right) Infective endocarditis can involve valve prostheses of all types. Hemodynamic consequences include both regurgitation and stenosis, depending on the size of vegetation and status of the cusps. Here, vegetations have resulted in perforation of one cusp, causing regurgitation.

(Left) In contrast, large infective vegetations may obstruct the valve orifice and result in significant prosthetic valve stenosis. (Right) Infective endocarditis may also involve mechanical valves, as in this case where bulky vegetations restrict mobility of the prosthetic leaflets, resulting in severe stenosis. Cultures and histologic sections should be obtained to confirm the infectious nature of the process and to identify the culprit microorganism.

(Left) Histologically, infective endocarditis involving a bovine pericardial bioprosthetic valve shows destruction of the cusp , with adherent fibrinrich thrombotic vegetation material containing numerous irregular "fuzzy" bacterial colonies . (Right) A tissue Gram stain highlights Gram-positive bacterial colonies within the thrombotic vegetation , and also within the partially destroyed cusp . Cultures confirmed the presence of Propionibacterium acnes.

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Gross Findings of Transcatheter Devices (Left) Catheter-deployed bioprosthetic valves are positioned within a diseased valve, without surgical removal thereof. Here, the atria have been removed, revealing a catheterdeployed bioprosthesis within a diseased aortic valve. Native cusps have been pushed aside by balloon dilatation prior to deployment of the device. (Right) Here, a catheter-deployed SAPIEN bioprosthetic valve is displayed alongside the excised calcified aortic valve cusps that surrounded it.

(Left) This patient with Tetralogy of Fallot underwent stenting of the RV outflow tract and deployment of a Melody valve . Devices should be assessed for deformation and strut fractures, which in this case were due to surgical removal. (Right) This catheter-deployed bioprosthesis was properly seated within the aortic valve annulus. Autopsy evaluation should include assessment of device position, expansion, cusp coaptation, and the potential for perivalvular leaks.

(Left) Catheter-deployed valves may be placed transfemorally or transapically, and must be properly oriented in the catheter sheath to prevent inverted (backward) deployment, as occurred in this unfortunate fatal case. Note anterior mitral leaflet . (Right) This mitral valve is shown from the ventricular side. Two MitraClip devices were used to fix the anterior leaflet to segments of the posterior leaflet. Note portion of aortic valve and the aortomitral continuity .

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

VALVE REPLACEMENT (INCLUDING TRANSCATHETER)

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

VENTRICULAR ASSIST DEVICES

This view demonstrates all components of a HeartMate II LVAD in situ at autopsy, including the sewing ring , inflow cannula , pump , outflow conduit , and driveline .

TERMINOLOGY

VAD Applications

Abbreviations

Right-sided (pulmonary) circulation generally improves with "unloading" of left ventricle In profound right heart failure, RVAD may be used In biventricular failure, BiVAD or TAH may be used

Ventricular assist device (VAD) Left ventricular assist device (LVAD) Right ventricular assist device (RVAD) Biventricular assist device (BiVAD) Total artificial heart (TAH)

CLINICAL ISSUES VADs in Clinical Practice

Use of VADs has increased exponentially since FDA approval of HeartMate II in USA in 2008

Support circulation during profound heart failure in 4

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The CardioWest TAH consists of artificial right and left ventricles, connected to the atria (behind device), main pulmonary artery , ascending aorta , and pneumatic drivelines .

settings Bridge to recovery: Temporary support until ventricular function is regained Useful for potentially reversible cardiac conditions, such as myocarditis, postpartum cardiomyopathy Bridge to transplant: Support until donor heart is available Destination therapy: Provides support indefinitely (for patients who are not candidates for transplantation) Increasingly becoming viable alternative to transplantation Survival with VAD is expected to approach that of transplantation (10-15 years average) in the future Avoids expense and complications of immunosuppression and rejection monitoring Bridge to decision: Support while determining candidacy for transplantation Later transitioned to either destination therapy or transplantation

LVAD most commonly used

Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)

Monitors VAD use and outcomes > 10,000 patients followed For continuous flow pumps, current actuarial survival is 80% at 1 year and 70% at 2 years

Research Opportunities Myocardial recovery

Multiple ongoing investigations exploring mechanisms of change during myocardial rest/ unloading afforded by VAD support Tissues commonly obtained at time of VAD implantation and at time of VAD removal (including not only at time of recovery or transplantation, but also at autopsy)

Types of VADs Extracorporeal

Pump and controller external to body (e.g., Berlin EXCOR Pediatric, BVS 5000) Clinically easier to inspect circuit and replace components in event of thrombus formation More invasive Higher infection risk Less portable Intracorporeal Intracardiac (e.g., HeartMate II, HeartWare HVAD) Direct cannulation of left ventricular apex for inflow, ascending aorta for outflow Only driveline exits body Lower infection risk

Key Facts Clinical Issues

4 main clinical settings: Bridge to recovery, bridge to transplant, destination therapy, bridge to decision Pros/cons of extracorporal VADs: Easier to inspect and replace components, but more invasive, carry higher infection risk, less portable Pros/cons of intracorporal VADs: Harder to replace components (only driveline exits body), but carry lower infection risk, are very portable Total artificial heart reserved for severe biventricular failure

Macroscopic Pathology

Photograph all extracorporeal and intracorporeal components in situ Examine skin at site(s) of device entry for infection; obtain samples for cultures Very portable with small battery packs and driver consoles Extracardiac (Tohuku EHAM) Pneumatically driven sheath placed around apex of left ventricle Sheath device compresses and relaxes, mimicking cardiac massage Still in developmental testing phase Total artificial heart (SynCardia CardioWest) Ventricles and all valves surgically removed, device sewn to atrial cuffs, and outflow cannulae anastomosed to proximal ascending aorta and main pulmonary artery Only pneumatic drivelines exit body FDA approved Freedom portable driver in 2014, enabling discharge from hospital Reserved for patients with severe biventricular failure

MACROSCOPIC FEATURES Photographic Documentation

Essential for medical, legal, and educational purposes Photograph all extracorporeal and intracorporeal components in situ

Photograph device components after disassembly Photograph thrombi, any other abnormalities

External Examination

Examine skin at site(s) of driveline or cannula entry

Inside body, evaluate device in situ for infection, malorientation of outflow conduit, etc.

Evaluate sheath at left ventricular apex for thrombus, pannus formation

Disassemble device and photograph components Open all conduits, examine blood contact surfaces for thrombus

Confirm cannula patency Examine pump chamber for surface abrasions, wear Document serial numbers and findings

Microscopic Pathology

Thrombus: Alternating layers of RBCs/WBCs and fibrin/platelets

Skin at device entry site(s): Dense neutrophilic inflammation/abscesses indicate infection; perform GMS and Gram stains to identify microorganisms Inflow cannula Pump Outflow conduit and anastomosis to ascending aorta Driveline Disassemble device and examine components Open all conduits and examine blood contact surfaces for thrombus Confirm cannula patency Examine pump chamber for surface abrasions, wear, etc. (using beam lighting and magnification or, if possible, pump disassembly) Examine housings and diaphragms Document serial numbers and any abnormalities

MICROSCOPIC PATHOLOGY Histologic Features Thrombus

Alternating layers of RBCs/WBCs and platelets/fibrin Must be distinguished from postmortem clot, which shows heavier blood components (WBCs) settling as single layer to one side of clot, in gravity-dependent fashion Skin at device entry and exit sites Dense neutrophilic inflammation and abscess formation indicate infection Special stains (e.g., GMS and Gram) to identify and characterize microorganisms

ANCILLARY TESTS

and exit for purulence, necrosis, erythema, and other signs of infection If signs of infection present, obtain samples for microbiologic culture

Radiograph and CT

Internal Examination

Scanning Electron Microscopy

Evaluate device in situ for signs of infection, disconnection of components, scarring with change in orientation of outflow conduit, other abnormalities Sewing ring and sheath at left ventricular apex Evaluate for thrombus and pannus formation

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

VENTRICULAR ASSIST DEVICES

Evaluate component integrity, mineralization, etc. Surface topography, biofilm, platelets, fibrin, abrasions, pitting, etc.

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VENTRICULAR ASSIST DEVICES

Summary of Pulsatile Flow Pump VADs Device Name

Manufacturer

Notes

Berlin EXCOR Pediatric

Berlin Heart

Extracorporeal, pediatric applications

CardioWest

SynCardia Systems, Inc.

Total artificial heart

Thoratec pVAD II

Thoratec

Short-to-midterm support, LVAD, RVAD, or BiVAD

Novacor LVAD

Novacor

1st generation, now discontinued

BVS 5000

Abiomed

1st generation, now discontinued

HeartMate XVE

Thoratec

1st generation, now discontinued

Summary of Continuous Flow Pump Devices Device Name

Manufacturer

Notes

HeartMate II

Thoratec

1st FDA approval, widest use in practice

HeartWare HVAD

HeartWare, Inc.

Small size allows intrapericardial implantation

Heart Assist 5

MicroMed Cardiovascular, Inc.

Direct flow sensing and management

DuraHeart

Terumo Heart, Inc.

Centrifugal flow magnetic levitation pump

2000 FlowMaker

Jarvik Heart, Inc.

Axial flow magnetically driven pump

Impella

Abiomed

Augments rather than replaces ventricle function

DeBakey Child

MicroMed Cardiovascular, Inc.

Small, intracorporeal, pediatric applications

Evaheart

Sun Medical

Centrifugal flow magnetic levitation pump

Synergy Pocket Micro-Pump

HeartWare, Inc. (formerly CircuLite, Inc.)

Size of AA battery, partial-assist of less sick patients

SELECTED REFERENCES 1.

McCandless SP et al: Comparing velour versus silicone interfaces at the driveline exit site of HeartMate II devices: infection rates, histopathology, and ultrastructural aspects. Cardiovasc Pathol. 24(2):71-5, 2015 2. Blitz A: Pump thrombosis-A riddle wrapped in a mystery inside an enigma. Ann Cardiothorac Surg. 3(5):450-71, 2014 3. Cheng A et al: Comparison of continuous-flow and pulsatile-flow left ventricular assist devices: is there an advantage to pulsatility? Ann Cardiothorac Surg. 3(6):573-81, 2014 4. Diakos NA et al: Myocardial atrophy and chronic mechanical unloading of the failing human heart: implications for cardiac assist device-induced myocardial recovery. J Am Coll Cardiol. 64(15):1602-12, 2014 5. Kirklin JK et al: Sixth INTERMACS annual report: a 10,000patient database. J Heart Lung Transplant. 33(6):555-64, 2014 6. Porepa LF et al: Destination therapy with left ventricular assist devices: for whom and when? Can J Cardiol. 30(3):296-303, 2014 7. Torregrossa G et al: SynCardia: the total artificial heart. Ann Cardiothorac Surg. 3(6):612-20, 2014 8. Xie A et al: Durability of continuous-flow left ventricular assist devices: a systematic review. Ann Cardiothorac Surg. 3(6):547-56, 2014 9. Carpenter BA et al: A brief review of ventricular assist devices and a recommended protocol for pathology evaluations. Cardiovasc Pathol. 22(5):408-15, 2013 10. Garbade J et al: Heart transplantation and left ventricular assist device therapy: two comparable options in end-stage heart failure? Clin Cardiol. 36(7):378-82, 2013 11. Peura JL et al: Recommendations for the use of mechanical circulatory support: device strategies and patient selection: a scientific statement from the American Heart Association. Circulation. 126(22):2648-67, 2012

12. Hannan MM et al: Working formulation for the standardization of definitions of infections in patients using ventricular assist devices. J Heart Lung Transplant. 30(4):375-84, 2011 13. Potapov EV et al: Managing long-term complications of left ventricular assist device therapy. Curr Opin Cardiol. 26(3):237-44, 2011 14. Rose AG et al: Pathology in patients with ventricular assist devices: a study of 21 autopsies, 24 ventricular apical core biopsies and 24 explanted hearts. Cardiovasc Pathol. 14(1):19-23, 2005

Gross Findings (Left) The HeartMate II LVAD is an intracorporeal device, with nearly all components inside the chest (note thoracotomy scar ). Only the driveline exits the body, which connects to an external driver console. This lowers the risk of infection and enables device portability. (Right) The CardioWest TAH is attached directly to the atria after surgical removal of the rest of the heart. Note artificial ventricles , drivelines , and Velcro connecting the ventricles.

(Left) The HeartWare HVAD is implantable within the pericardium, with the pump attached directly to the left ventricular apex and the outflow conduit attached to the ascending aorta. The driveline is partially hidden under the specimen in this view. (Right) Here, the heart has been largely removed from the HeartWare HVAD, revealing the device’s components, including the pump , outflow conduit , and long coiled driveline with adherent subcutaneous tissue.

(Left) Disassembly is essential for identifying thrombi, damage, and other device abnormalities. Here, the inflow cannula , pump , outflow conduit , and driveline of a HeartMate II LVAD are all seen. (Right) This view into the pump chamber of a HeartMate II LVAD demonstrates old thrombus surrounding the driveshaft above the impeller. Thrombus formation is an infrequent but important complication, and examination of VADs must include a careful search for thrombus.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

VENTRICULAR ASSIST DEVICES

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THORACIC AORTIC ANEURYSM REPAIR

This thoracic aneurysm wall shows degenerative changes in the media. The media demonstrates loss of staining of nuclei of smooth muscle cells and increase in proteoglycans . (From DP: Cardiovascular.)

TERMINOLOGY TAA repair, TEVAR (thoracic endovascular aortic repair), OTAR (open thoracic aortic repair),

Definitions

Aneurysm: Localized pathologic dilatation of vessel

ETIOLOGY/PATHOGENESIS Pathogenesis

May be syndromic or nonsyndromic Syndromic: Marfan syndrome (fibrillin 1), vascular Ehlers Danlos, Loeys-Dietz syndrome (types 1 and 2), familial thoracic aortic aneurysm syndrome Nonsyndromic: 15% of patients with nonsyndromic TAA have positive family history Genes associated with nonsyndromic TAA include ACTA 2, MYH 11, TGFBRI and TGFBRII These genes may be associated with TGF B signaling, indicating similar pathogenesis to syndromic TAA Bicuspid aortic valve (BAV) 1.3% of general population has BAV and 14% of patients with TAA have bicuspid aortic valve Valve function may be stenotic, regurgitant, or normal, suggesting factors other than hemodynamics play a role in formation of TAA with BAV

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Proliferative endarteritis of vasa vasorum ischemic injury to vascular media aneurysmal dilatation

Abbreviations

wall at least 50% > normal, true aneurysm contains all layers of vessel wall Aortic size increase with age 1-2 mm/year Normal ascending aorta measurements, generally < 3.5 cm; descending thoracic aorta generally < 2.5 cm

This ascending aortic aneurysm (heart , pulmonary artery ) required repair due to its large size. (From DP: Cardiovascular.)

Infection

Historically syphilitic aortitis in tertiary syphilis was an important cause of TAA; now rare

CLINICAL ISSUES Epidemiology Incidence

TAA incidence is 10.4/100,000 person-years

Presentation

Usually silent until complications (dissection/rupture)

Risk of rupture with size; > 6 cm has 30% risk of rupture/dissection Rupture presents with acute pain, hypotension/ shock Pain location varies with site of aneurysm: Ascending: Anterior chest pain; arch: Neck pain; descending: Back pain between scapulae Chronic pain is seen with large aneurysms due to distension and compression of surrounding structures Large aneurysms may present with superior vena cava syndrome First report of SVC syndrome was due to syphilitic ascending aortic aneurysm Now malignancy (lung carcinoma) most common cause for SVC syndrome but 40% have benign cause Syndrome caused by partial to complete obstruction to blood flow in superior vena cava thrombosis of vessel Symptoms include dyspnea, facial swelling, facial congestion, cough, arm swelling Post-repair complications include Shock, valvular insufficiency, stroke, embolic phenomena, ischemic myocardial, gastrointestinal and hepatic injury, acute tubular injury/necrosis, infection and ischemic spinal cord injury

Key Facts Terminology

Aneurysm: Localized pathologic dilatation of vessel wall at least 50% > normal, true aneurysm contains all layers of vessel wall

Etiology

May be syndromic or nonsyndromic Syndromic: Marfan syndrome (fibrillin 1), vascular Ehlers Danlos, Loeys Dietz syndrome (types 1 and 2), familial thoracic aortic aneurysm syndrome Nonsyndromic: 15% of patients with nonsyndromic TAA have positive family history 1.3% of general population has BAV and 14% of patients with TAA have bicuspid aortic valve

thoracoabdominal, or descending aortic aneurysm repair

Treatment

Surgical approaches

Indications for repair Size, growth rate, symptoms Types of repair Endovascular: Fabric (polyester or PTFE)-covered metallic (nitinol, stainless steel) stent is deployed across aneurysm to exclude it from aortic blood flow leading to aneurysm thrombosis and remodeling Most commonly used for descending thoracic aneurysms, ascending and aortic arch hybrid procedures (multiple grafts, combined endovascular and open procedures) used for ascending and arch repair Open: Ascending and arch repair with coronary artery and branch vessel reimplantation aortic valve replacement (Bentall procedure: Ascending aortic aneurysm graft with aortic valve replacement and coronary artery reimplantation)

IMAGE FINDINGS Radiographic Findings

Postmortem chest radiograph may be valuable and reveal endovascular repair (stents visible), open repair (grafts should be visible), aortic dilatation, and pleural effusions visible

MACROSCOPIC FEATURES External Examination

Pallor (hemorrhagic shock from rupture), petechiae (DIC following rupture and hemorrhage), Sternotomy incision (OTAR), groin incision (TEVAR) Facial congestion and swelling (SVC syndrome) Syndromic features

Clinical Issues

Usually silent until complications (dissection/ rupture)

Risk of rupture with size; > 6 cm has 30% risk of rupture/dissection

Indications for repair: Size, growth rate, symptoms Endovascular repair: Fabric (polyester or PTFE)covered metallic (nitinol, stainless steel) stent is deployed across aneurysm to exclude it from aortic blood flow leading to aneurysm thrombosis and remodeling Open repair: Ascending and arch repair with coronary artery and branch vessel reimplantation aortic valve replacement (Bentall procedure: Ascending aortic aneurysm graft with aortic valve replacement and coronary artery reimplantation)

Marfan (thin, long limbs; arm span > height; long digits; pectus excavatum) Loeys-Dietz (type 1 overlaps with Marfan with craniofacial anomalies bifid uvula, cleft palate hypertelorism), type 2 with overlap with Marfan and vascular Ehlers Danlos (usually only bifid uvula, pectus, joint laxity and long digits, and bruising) Vascular Ehlers Danlos (bruising, velvety translucent skin, small lax joints)

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

THORACIC AORTIC ANEURYSM REPAIR

Internal Examination

In situ documentation of graft type, segment of aorta grafted (open or endovascular), length and patency of graft, patency of branch vessels including coronary arteries in cases of ascending aneurysm, status of nongrafted aorta, presence of intramural hematoma (dissection in 15% of TAA) Procure material for microbiologic culture studies if clinically indicated (suspected graft infection) immediately upon opening chest cavity Anastomotic integrity assessed by inspection and water infusion into aorta if concern for anastomotic integrity

Organ Examination Aorta and heart

Open aorta from distal aspect after inspecting graft and anastomoses and branch vessels Section nongrafted aorta and anastomoses; Dacron graft material can be processed for histologic analysis Ascending aorta: Inspect any coronary graft ostia, or coronary buttons (reimplanted native coronary ostia) Coronary reimplantation or bypass may be necessary in ascending aortic repair Examine coronary arteries for evidence of dissection, surgical injury Inspect aortic valve from aortic aspect Native valve: Cusp number (check for BAV) and coaptation, surgical injury (suture, etc.), surgical

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

THORACIC AORTIC ANEURYSM REPAIR

repair (pledgeted sutures to resuspend valve cusps), vegetation Bioprosthetic valve: May be part of ascending aorta replacement or separate; look for cusp integrity, thrombosis, surgical injury, vegetation Heart Size and weight: Dilated left ventricle with eccentric hypertrophy in aortic valve insufficiency, concentric hypertrophy with aortic stenosis and hypertension Myocardial infarction: May be multifactorial: Operative stress, surgical injury, embolic, underlying coronary atherosclerosis Respiratory Cardiogenic pulmonary edema (congestive heart failure from aortic valve insufficiency, perioperative ischemic injury etc.) Noncardiogenic pulmonary edema: Multifactorial: Operative stress, intercurrent sepsis, shock (hypovolemic from hemorrhage or cardiogenic), aspiration Pneumonia: Aspiration Gastrointestinal Ischemic injury (shock) Hepatobiliary Congestion (congestive heart failure from aortic valve insufficiency), necrosis (shock liver) Acute pancreatitis (uncommon complication of cardiopulmonary bypass) Genitourinary Acute tubular injury (operative stress, hypovolemic shock) Central and peripheral nervous system Spinal cord injury (ischemic) with descending aneurysm repair or arch repair with distal graft tunneled into descending aorta; examination of thoracic cord is important in these cases Appearance of CNS and spinal cord infarcts varies with duration from injury, and presence or absence of hemorrhage

MICROSCOPIC PATHOLOGY Histologic Features Heart and aorta

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Anastomotic sections: Adventitial granulation tissue and fibrosis with longer duration grafts, abscess if superimposed infection Aortic sections: Intramural hematoma (dissection) acute or chronic, cystic medial degeneration, smooth muscle cell loss If aneurysm from syphilitic aortitis (rare), intimal proliferation of adventitial vessels (vasa vasora), plasma cell-rich inflammation and laminar necrosis of media due to ischemia Heart with hypertrophy and areas of interstitial fibrosis in cases with aortic valve insufficiency, varying stages of acute and healing coagulative myocyte necrosis in cases with infarction

May see foreign material (suture, etc.) embolization related to surgery Respiratory system Intraalveolar pale pink fluid (cardiogenic pulmonary edema); fibrin layering along alveolar septal walls evidence of organization (noncardiogenic pulmonary edema), intrabronchial and intra alveolar acute inflammation in pneumonia With aspiration may see intra-airway or -alveolar gastric content or aspirated squames from oral cavity and multinucleated giant cells with chronic aspiration Gastrointestinal system Varying severity of ischemic injury with coagulative necrosis of mucosa to serosa (severe case), submucosal vascular thrombosis, may see atheroemboli or foreign material (suture) emboli related to operative intervention and catheterization Hepatobiliary system Centrilobular hepatocyte necrosis and congestion; larger areas of necrosis affecting entire lobule and bridging from lobule to lobule in more severe shock Coagulative necrosis of pancreatic parenchyma with fibrin thrombi in vessels in bypass related acute pancreatitis Usually seen in association with other shock changes such as hepatic necrosis, intestinal ischemia, and acute tubular injury Genitourinary system Loss of brush border of distal and proximal tubular epithelial cells with coagulative necrosis in more severe cases of acute tubular injury/necrosis Central and peripheral nervous system Cerebral infarct appearance varies with time from ischemic insult 12 hours: Red neurons, vasogenic edema 48 hours: Neutrophilic infiltrate begins to decrease and phagocytes increase to become prominent cell type over ensuing weeks, reactive astrocytes appear at edge of infarct Spinal cord infarct will have similar features

DIFFERENTIAL DIAGNOSIS Pseudoaneurysm

Contained rupture of aorta with communication with vessel lumen Contains hematoma surrounded by granulation tissue or fibrous tissue depending on age of pseudoaneurysm Does not contain layers of vessel wall

SELECTED REFERENCES 1.

Arnaoutakis DJ et al: Cohort comparison of thoracic endovascular aortic repair with open thoracic aortic repair using modern end-organ preservation strategies. Ann Vasc Surg. 29(5):882-90, 2015 Bicknell C et al: Aortic disease: thoracic endovascular aortic repair. Heart. 101(8):586-591, 2015

Imaging and Repair of Thoracic Aortic Aneurysms (Left) Enhanced CT of the chest shows a large ascending aortic aneurysm . There is atherosclerotic plaque in the descending aorta but the lumen is of normal caliber. (Right) This is an in situ view of a large ascending aortic aneurysm prior to repair (heart ).

(Left) This aortic arch is markedly dilated and the blue discoloration indicates an aortic dissection complicating this arch aneurysm. (Right) Aortic arch repair often includes repair of the arch vessels. Here they are replaced with grafts . If the ostia and the proximal arch vessels are intact, the vessel-bearing portion of the arch can also sometimes be resected and attached to the arch graft, similar to coronary buttons.

(Left) Saphenous vein bypass grafts can be attached to ascending aortic grafts to perform a simultaneous coronary artery bypass procedure. In this case, 2 grafts are attached proximally and veinto-vein Y grafts are used to bypass additional vessels. (Right) In this case of aortic root replacement, the coronary arteries are being reattached to the ascending graft as a coronary button that contains the coronary ostium and a portion of the surrounding aortic wall.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

THORACIC AORTIC ANEURYSM REPAIR

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

THORACIC AORTIC ANEURYSM REPAIR

Imaging and Repair of Thoracic Aortic Aneurysms (Left) CT angiogram in a patient with Marfan syndrome and acute chest syndrome shows the classic "tulip bulb" appearance due to annuloaortic ectasia. Other terms describing this appearance include "onion bulb," "pear-shaped," and "Florence flask." (From DI: Cardiovascular.) (Right) Graphic compares a normal ascending aorta (left) with a well-defined sinotubular junction and annuloaortic ectasia with sinotubular junction effacement (right) as seen in Marfan syndrome.

(Left) This aortic root and ascending aortic aneurysm is being replaced with a valved conduit so the aortic valve, root, and ascending aorta are replaced simultaneously. In this photograph, the proximal suturing of the valve into the root is being performed. Multiple sutures will anastomose the sewing ring of the valve onto the root. (Courtesy J. Plate, MD & E. Pantin, MD). (Right) The coronary buttons have been anastomosed to the ascending aortic graft.

(Left) This is the outflow view of an aortic valve that has been re-suspended with 3 commissure pledgeted sutures . There is excellent coaptation of the valve cusps after resuspension. (Right) Sagittal reconstructed CT shows a large descending thoracic aneurysm . Descending aortic aneurysms are easier to repair with endografts that ascending aneurysms. (From DI: Chest.)

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Imaging and Repair of Thoracic Aortic Aneurysms (Left) Enhanced CT of the chest shows a large ruptured thoracic aortic aneurysm. Contrast is seen in the lumen of the aneurysm , with a large amount of extravasated blood and hematoma in the mediastinum and right hemithorax . (From DI: Chest.) (Right) This is an open repair of a descending thoracic aneurysm with a Dacron graft . Repair of these aneurysms has a risk of paraplegia due to spinal cord ischemic injury. In autopsies following this type of repair, examination of the thoracic spinal cord is indicated.

(Left) Graphic shows a descending thoracic aneurysm repaired with an endograft. The endograft struts attach to the aortic wall. The body is composed of fabric-covered selfexpanding stents . (Right) 3D reconstruction shows a thoracoabdominal aneurysm after endograft repair . (From DI: Procedures.) The location of endografts should be determined by chart review, premortem imaging review &/or postmortem/ specimen imaging prior to aortic dissection to avoid iatrogenic injury to the graft.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

THORACIC AORTIC ANEURYSM REPAIR

(Left) Angiogram shows a large saccular aneurysm . This is likely a pseudoaneurysm that represents a contained periaortic hematoma with retained communication to the aortic lumen. (Right) Angiogram in the same case is shown after endograft repair . The endograft excluded the pseudoaneurysm from the aortic blood flow. (From DI: Procedures.)

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

PANCREAS RESECTION

Diffuse peritonitis with green-yellow exudates covering the serosal/peritoneal surfaces occurred status post distal pancreatectomy. Jejunostomy tube and drain were in place.

TERMINOLOGY Definitions

Whipple procedure (pancreaticoduodenectomy): Resection of pancreatic head and uncinate process, distal stomach, duodenum, proximal jejunum, cholecystectomy Anastomoses from proximal to distal: End-to-side pancreaticojejunostomy, hepaticojejunostomy (hepatic bile duct), end-to-side gastrojejunostomy Variant: Pylorus-preserving Whipple: Stomach and proximal 1st portion of duodenum are preserved with end-to-side duodenojejunostomy Distal pancreatectomy: Resection of body and tail of pancreas, splenectomy, suture/staple closure of pancreatic stump Central pancreatectomy: Segmental resection of isthmus or body of pancreas Distal pancreaticojejunostomy with Roux-en-Y jejunojejunostomy or distal pancreaticogastrostomy (gastrointestinal tract remains intact), closure of proximal pancreatic stump Usually performed for benign or premalignant/lowgrade malignant tumors Roux-en-Y technique: Jejunum is divided, distal pancreas anastomosed to distal end of jejunum to create Y limb, proximal jejunum anastomosed to distal jejunum Total pancreatectomy: Pancreaticoduodenectomy with resection of entire pancreas splenectomy

ETIOLOGY/PATHOGENESIS Indications for Resection

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Malignant tumors: Pancreatic ductal adenocarcinoma, common bile duct adenocarcinoma, ampullary or duodenal adenocarcinoma, acinar cell carcinoma,

The posterior surface of the organ block in the same patient showed red-black hemorrhagic necrotic retroperitoneal soft tissue due to postoperative acute pancreatitis.

pancreatic endocrine neoplasm, solid pseudopapillary neoplasm, pancreatoblastoma Premalignant tumors: Intraductal papillary mucinous neoplasm, mucinous cystic neoplasm Benign tumors: Serous or acinar cell cystic neoplasm, large duodenal adenoma Involvement by extrapancreatic malignancy: Gastric or colonic adenocarcinoma, metastasis (rare) Nonneoplastic: Chronic/autoimmune pancreatitis, pseudocyst, trauma

CLINICAL ISSUES Presentation Symptoms

Abdominal pain, nausea, vomiting, diarrhea/ steatorrhea, melena, hematemesis, dyspnea Signs Fever, tachycardia, oliguria, hypotension, peritoneal signs, jaundice/scleral icterus, hypovolemic/septic shock Important elements of chart review Type of operation and anastomoses performed, surgical pathology reports of resected specimens, intra-/postoperative complications interventions, (neo)adjuvant chemotherapy/radiation Comorbidities, coagulation disorders, medications (e.g., anticoagulants, antiplatelet agents)

Laboratory Tests

hemoglobin and hematocrit, (+) fecal occult blood Leukocytosis, lactic acidosis, hyperglycemia amylase, lipase, blood urea nitrogen, creatinine, transaminases, alkaline phosphatase, and C-reactive protein tumor markers (e.g., CA19-9, chromogranin-A) amylase or bilirubin in effusions, intraabdominal collections, or drain outputs (+) blood, fluid collection, wound cultures

Key Facts Terminology

Types of pancreas resection: Whipple procedure (pancreaticoduodenectomy), distal, central, or total pancreatectomy

Etiology

Malignant, premalignant, or benign tumors, chronic/ autoimmune pancreatitis, pseudocysts, trauma

Clinical Issues

Complications reported in up to 50% after any type of pancreas resection Early complications: Pancreatic fistula/leak, bleeding, delayed gastric emptying, biliary leak, acute pancreatitis, infection, ischemia Early or late complications: Tumor recurrence

Prognosis

Mortality rate

Whipple: < 10% Distal pancreatectomy: < 5% Central pancreatectomy: Very low Causes of death Pancreatic fistula/leak Vascular/bleeding Tumor progression Infection (wound, intraabdominal, pneumonia) sepsis Acute/hemorrhagic pancreatitis, intestinal ischemia, cardiac related

Complications

Reported in up to 50% after any type of pancreas resection

Risk factors: Low-volume center, low-volume surgeon Early complications

Pancreatic leak/fistula: Incidence is 10-30%; can lead to bleeding or intraabdominal abscess sepsis Risk factors include soft parenchyma, obesity (fatty parenchyma), and pancreatic duct diameter < 3 mm Delayed gastric emptying: Incidence is 20-50% after Whipple Bleeding: Incidence is up to 20%, due to vascular injury, anastomotic ulcers/dehiscence, fistulas, pseudoaneurysms Biliary complications: Incidence varies up to 10%, bile leak, cholangitis, fistulas, bile duct strictures/ stenosis Acute pancreatitis: Incidence is 2-3% Infections: Intraabdominal, wound, or pneumonia sepsis Ischemic complications: Incidence varies; arterial stenosis, trauma, or kinking intestinal or biliary ischemia Other organ failure: Acute renal, respiratory, or liver failure; may be multifactorial Early or late complications

Late complications: Pancreatic exocrine/endocrine insufficiency, infection

Macroscopic Pathology

Examine upper gastrointestinal tract including remnant pancreas, biliary tract, and liver (if part of anastomosis) in situ for anastomotic leaks/strictures, fistulas Remove en block, then open

Diagnostic Checklist

Immediate cause of death and how it relates to surgery

Postsurgical complications and risk factors for developing complications

Presence of residual/recurrent/metastatic tumor

Tumor recurrence: Incidence varies depending on tumor type, local vs. distant Late complications Pancreatic endocrine insufficiency new-onset diabetes mellitus Pancreatic exocrine insufficiency steatorrhea, weight loss, vitamin deficiencies Post splenectomy infection (encapsulated bacteria)

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

PANCREAS RESECTION

IMAGE FINDINGS CT Findings

Peripancreatic/intraabdominal fluid collections, ascites, hemoperitoneum, free air, intestinal obstruction Pulmonary infiltrates, pleural/pericardial effusions Masses, lymphadenopathy, evidence of metastatic disease

CT Angiography

Identify/treat active bleeding, vascular injury, fistulas, pseudoaneurysms

Upper Gastrointestinal Series/Contrast Swallow Anastomotic leaks, strictures, ulcers

MACROSCOPIC FEATURES External Examination

Surgical interventions: Wound status, drains Sepsis changes: Petechiae, jaundice, acrocyanosis Hemorrhagic changes: Pallor

Internal Examination

Pleural/pericardial effusions Ascites, hemoperitoneum, fluid collections/abscesses, peritonitis (green-yellow fibrinous peritoneal/serosal surfaces) Peritoneal/serosal/mesenteric tumor studding/caking, lymphadenopathy

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

PANCREAS RESECTION Organ Examination

Examine upper gastrointestinal tract including remnant pancreas, biliary tract, and liver (if part of anastomosis) in situ for anastomotic leaks/strictures, fistulas Remove en block, then open Stomach and small intestine Mucosal ulcers, anastomotic necrosis dehiscence and perforation, perigastric/intestinal collections, abscesses, fistulas, strictures, adhesions Ischemic changes: Dusky, hemorrhagic mucosa ulcers, green-yellow pseudomembranes, perforations Remnant pancreas Indurated, edematous parenchyma hemorrhage, necrosis, peripancreatic abscesses, pseudocysts Suture/staple line dehiscence/leak Masses/cystic lesions in parenchyma or pancreatic bed Colon: Adhesions, ischemic changes Extrahepatic bile ducts: Mucosal erosions/ulcers, purulent debris, stenosis/strictures, fistulas, anastomotic dehiscence Liver: Congestion, patchy necrosis, cholestasis, abscesses, strictures/dilatations of intrahepatic bile ducts, masses Vascular: Status of stents/anastomoses/ligations, stenosis/strictures, thrombosis, pseudoaneurysms, kinking Heart: Subendocardial/myocardial mottling, pale soft areas hyperemic borders, nonbacterial thrombotic endocarditis (malignancy associated) Lungs: Consolidation, edema/congestion, abscesses, metastatic tumor, thromboemboli Kidneys: Cortical pallor, medullary congestion Venous system: Check for thrombi, presence of IVC filter or ligation "Milk" lower extremities to check for venous thrombi (free-flowing blood = nonobstructed venous system, no blood flow = venous thrombosis)

Sepsis changes: Hepatocellular, canalicular, and ductular cholestasis Shock changes: Centrilobular/perivenular congestion and hepatocellular necrosis Acute cholangitis: Bile duct intraluminal and intraepithelial acute inflammation, duct rupture and portal abscesses, sinusoidal neutrophils lobular abscesses, parenchymal necrosis Large bile duct obstruction: Portal tract edema, chronic inflammation, periportal ductular reaction with associated neutrophils, cholestasis, bile infarcts Metastatic tumor Heart: Subendocardial/myocardial contraction band injury, coagulative necrosis, edema, hemorrhage, neutrophils and macrophages Lungs: Bronchopneumonia, abscesses, diffuse alveolar damage (alveolar hyaline membranes, neutrophils, fibrin deposition, edema), metastatic tumor, pulmonary thromboemboli Kidneys: Dilated tubules and tubal epithelial necrosis/ sloughing (acute tubular injury)

ANCILLARY TESTS Microbiology

Postmortem blood, fluid collection, tissue, and wound cultures if not done premortem

DIAGNOSTIC CHECKLIST Reporting Criteria

Immediate cause of death and how/if it relates to surgery

Postsurgical complications and risk factors for developing complications

Presence of residual/recurrent/metastatic tumor and paraneoplastic effects If autopsy findings change original stage of tumor, new stage should be reported Correlation of postmortem and premortem tumor pathology

MICROSCOPIC PATHOLOGY Histologic Features

Stomach, small intestine, and colon

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Mucosal erosions/ulcers, transmural inflammation necrosis, acute/organizing serositis, fibroinflammatory adhesions Ischemic injury: Epithelial sloughing/necrosis, ulcers, hemorrhage, transmural necrosis, mucopurulent exudate (pseudomembranes), remaining crypts/glands look withered Serosal/mesenteric tumor deposits Remnant pancreas Acute inflammation, edema, hemorrhage, fat necrosis Recurrent/residual tumor Extrahepatic bile ducts: Mucosal erosions/ulcers, inflammation, mural fibrosis, degenerative/ regenerative epithelial changes Liver

SELECTED REFERENCES 1. 2.

Kim JH et al: Surgical outcomes of distal pancreatectomy. Hepatogastroenterology. 60(126):1263-7, 2013 Lermite E et al: Complications after pancreatic resection: diagnosis, prevention and management. Clin Res Hepatol Gastroenterol. 37(3):230-9, 2013 Bock EA et al: Late complications after pancreaticoduodenectomy with pancreaticogastrostomy. J Gastrointest Surg. 16(5):914-9, 2012 Shah OJ et al: Central pancreatectomy: a new technique for resection of selected pancreatic tumors. Hepatobiliary Pancreat Dis Int. 8(1):93-6, 2009

Graphic, Gross, and Microscopic Features (Left) The pyloruspreserving Whipple procedure has the following anastomoses: Remnant pancreaticojejunostomy , hepatic bile duct hepaticojejunostomy , and duodenojejunostomy . (Right) Residual pancreatic ductal adenocarcinoma was identified invading the portal vein and surrounding soft tissue with perineural invasion in a patient who died 4 days after a Whipple procedure. This upstaged the original pathologic tumor stage from a pT2 to a pT4.

(Left) Ischemic liver necrosis characterized by patchy pale tan soft parenchyma developed due to hemorrhagic shock secondary to rupture of a gastroduodenal artery stump pseudoaneurysm status post distal pancreatectomy. (Right) Sepsis changes in the liver are characterized by green-brown bile plugs in the canalicular spaces and hepatocellular cholestasis . These findings were present in the patient with peritonitis and sepsis status post distal pancreatectomy.

(Left) This lung abscess was discovered at autopsy in a patient who developed postoperative pneumonia after a Whipple procedure. Postmortem culture grew Klebsiella pneumoniae. (Right) Section through the gastrojejunostomy site in a patient status post Whipple procedure shows a mucosal ulcer , granulation tissue, and foreign body giant cell reaction to suture material at the anastomosis. Intact gastric mucosa is present on one side of the anastomosis.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

PANCREAS RESECTION

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

GASTRECTOMY AND ESOPHAGECTOMY

This patient died during a transhiatal esophagectomy as a result of transection of the right intercostal artery at the level of T6 as demonstrated by the probe . (Courtesy J. Hon, MD.)

TERMINOLOGY

CLINICAL ISSUES

Definitions

Presentation

esophagus; many different surgical approaches (transhiatal, thoracoabdominal, thoracotomy, minimally invasive, 3-hole technique) conduit such as small intestine or colon Ivor Lewis esophagogastrectomy: 2-stage surgical procedure composed of subcostal abdominal incision followed by a right thoracotomy Performed for tumors of distal esophagus, gastroesophageal (GE) junction, or proximal stomach Gastrectomy: Resection of part or all of stomach; many different surgical approaches (partial, distal, subtotal, or total resection, Billroth I or II or Rouxen-Y anastomosis) Billroth I operation (gastroduodenostomy): Anastomosis of proximal stomach directly to duodenum after distal gastrectomy Billroth II operation (gastrojejunostomy): Anastomosis of end of remnant stomach to side of proximal jejunum after partial or subtotal gastrectomy Roux-en-Y anastomosis: Anastomosis of end of remnant stomach or esophagus to a portion of jejunum with creation of a jejunojejunostomy after a partial or subtotal gastrectomy

Cough, dyspnea, tachypnea, chest pain, palpitations, hemoptysis Nausea, vomiting, hematemesis, abdominal pain, melena Signs Fever, tachycardia, arrhythmia, altered mental status Hypotension, hypoxemia, hypovolemic/septic shock, peritoneal signs Important elements of chart review Indication for surgery/underlying disease, comorbidities Type of operation performed, intraoperative complications, postoperative course Surgical pathology reports for confirmation and extent of disease

Esophagectomy: Partial or total resection of

ETIOLOGY/PATHOGENESIS Indications for Resection

Esophagectomy: Benign/malignant neoplasms,

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A right-sided hemothorax containing 1,700 mL of blood was found in the same patient as a result of transection of the intercostal artery at ~ 3 mm from the aortic origin.

corrosive/peptic strictures, achalasia, perforation Gastrectomy: Benign/malignant neoplasms, bleeding or perforation due to peptic ulcer disease, pyloric stenosis, gastric outlet obstruction

Symptoms

Laboratory Tests

hemoglobin/hematocrit, (+) fecal occult blood Leukocytosis, lactic acidosis creatine kinase-MB, troponin, BUN, creatinine, amylase and lipase, (+) D-dimer

Chylous effusion: Triglycerides > 110 mg/dL, ratio of effusion fluid to serum triglycerides > 1.0, ratio of effusion fluid to serum cholesterol < 1.0 (+) blood, wound, fluid collection cultures (e.g., bronchial washes, effusions, abscesses)

Prognosis

Mortality rate

Esophagectomy: Up to 22%, average ~ 2.5% Gastrectomy: Up to 14%, average ~ 2% Causes of death Post esophagectomy Pulmonary (2/3 of postoperative deaths): Pneumonia aspiration due to recurrent

Key Facts Clinical Issues

Complications reported in up to 60% of cases following both esophagectomy and gastrectomy

Risk factors for complications: age, procedure

performed at low-volume center, male sex, comorbidities Mortality rate: Esophagectomy: Up to 22%, average ~ 2.5%; gastrectomy: Up to 14%, average ~ 2% Causes of death post esophagectomy Pulmonary: Pneumonia aspiration, tracheoesophageal fistula, acute respiratory distress syndrome, pulmonary embolism Anastomotic/conduit related: Dehiscence mediastinitis, ischemia/necrosis perforation Cardiovascular: Myocardial infarction, atrial fibrillation/other arrhythmia

laryngeal nerve injury/other swallowing disorder/ tracheoesophageal fistula, acute respiratory distress syndrome, pulmonary embolism Anastomotic/conduit related: Dehiscence mediastinitis, ischemia/necrosis perforation sepsis Cardiovascular: Myocardial infarction, atrial fibrillation/other arrhythmia, vascular injury Chylothorax due to thoracic duct injury (rare) protein loss sepsis, acidosis, electrolyte abnormalities Arterial-esophageal fistula Others: Cerebral infarction, sepsis, multiorgan failure Post gastrectomy Anastomotic: Dehiscence/ischemia/necrosis intraabdominal abscess, peritonitis sepsis Intraabdominal: Ileus, intestinal obstruction, fistula formation, perforation sepsis Pulmonary: Pneumonia, acute respiratory distress syndrome, pulmonary embolism

Complications

Complications reported in up to 60% of cases following both esophagectomy and gastrectomy Risk factors for complications: age, procedure performed at low-volume center, male sex, comorbidities Early complications Esophagectomy: Pulmonary/intrathoracic (most common), anastomotic/conduit related, cardiovascular, infection Ivor Lewis procedure: Pulmonary, anastomotic, infection Gastrectomy: Anastomotic (most common), intraabdominal, pulmonary, infection Long-term complications Esophagectomy/Ivor Lewis procedure: Strictures, diaphragmatic hernia, dumping syndrome, reflux esophagitis Barrett esophagus dysplasia adenocarcinoma

Others: Arterial-esophageal fistula, chylothorax, cerebrovascular accident, sepsis, multiorgan failure Causes of death post gastrectomy Anastomotic: Dehiscence/ischemia/necrosis intraabdominal abscess, peritonitis sepsis Intraabdominal: Ileus, intestinal obstruction, fistula formation, perforation sepsis Pulmonary: Pneumonia, acute respiratory distress syndrome, pulmonary embolism

Reporting Considerations

Immediate cause of death and how it relates to surgery

Other postsurgical complications Risk factors for developing postsurgical complications Presence of residual/metastatic disease

Gastrectomy Malnutrition, vitamin B12/iron deficiency anemia, fat maldigestion steatorrhea and fatsoluble vitamin deficiency, osteoporosis Reflux esophagitis Barrett esophagus dysplasia adenocarcinoma Bile reflux, remnant gastritis remnant/stump adenocarcinoma (may be Epstein-Barr virus [EBV] associated)

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

GASTRECTOMY AND ESOPHAGECTOMY

IMAGE FINDINGS CT Findings

Pulmonary infiltrates, pleural/pericardial effusions, mediastinal fluid collections, or pneumomediastinum

Intraabdominal abscess, free air, ascites, ileus/intestinal obstruction

Upper GI Series/Contrast Swallow

Abnormal swallowing, anastomotic leaks, strictures, ulcers

CT Angiogram

Identify/treat active bleeding, vascular injury, fistulas Pulmonary angiogram for pulmonary embolism

MACROSCOPIC FEATURES External Examination

Surgical interventions: Incisions, wound status, drains Sepsis changes: Petechiae, jaundice, acrocyanosis Hemorrhagic changes: Pallor

Internal Examination

Pleural effusions, empyema, hemothorax (examine thoracic vessels in situ if present)

Chylothorax: White, turbid, milky effusion + thoracic duct injury (examine in situ, best viewed from left side) Pericardial effusion Mediastinitis: Fibrinopurulent exudate, abscesses

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

GASTRECTOMY AND ESOPHAGECTOMY Ascites, peritonitis (green-tan fibrinous peritoneal/ serosal surfaces) Metastatic disease, lymphadenopathy

Organ Examination

Examine upper GI tract in situ for fistulas/anastomotic leaks: May transect cervical esophagus above anastomosis and perfuse with water/dye to assess for leaks Remove esophagus, stomach, duodenum jejunum (if part of anastomosis) en bloc, then open Esophagus: Anastomotic ulcer, necrosis dehiscence, perforation, arterial/tracheoesophageal fistula, strictures, mucosal erythema/erosions, tan/ salmon-colored mucosa (Barrett esophagus), masses Stomach: Mucosal erythema/erosions, anastomotic ulcer, necrosis dehiscence, perforation, perigastric abscesses, fistulas, masses Small and large intestine: Obstruction (functional vs. adhesions/strictures/masses), fistulas, ischemic changes (dusky, hemorrhagic mucosa ulcers, green-yellow pseudomembranes, perforations) Pancreas: Indurated, edematous pancreas hemorrhage, necrosis, peripancreatic abscesses, pseudocysts, fat necrosis Lungs: Consolidation, abscesses (R > L in cases of aspiration), edema/congestion, thromboemboli, wedge-shaped hemorrhagic infarct, fibrinous pleural exudate Cardiovascular: Subendocardial/myocardial mottling, pale yellow discoloration surrounding hyperemia (infarction), evidence of vascular injury/ pseudoaneurysms/rupture Kidneys: Cortical pallor, medullary congestion Liver: Congestion, patchy necrosis, cholestasis Brain: Infarcts (areas of softening with tan discoloration or hemorrhage)

MICROSCOPIC PATHOLOGY Histologic Features Gastrointestinal tract

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Anastomotic mucosal ulcers, transmural acute inflammation necrosis, acute/organizing serositis, fibroinflammatory adhesions Reflux esophagitis, Barrett esophagus, dysplasia adenocarcinoma Gastric remnant chronic gastritis/reactive gastropathy intestinal metaplasia, dysplasia adenocarcinoma Ischemic enterocolitis: Epithelial necrosis/sloughing, mucosal ulcers, lamina propria/submucosal hemorrhage, transmural necrosis, mucopurulent exudate (pseudomembranes), "withered" crypts Acute pancreatitis with neutrophils, edema, hemorrhage, adjacent fat necrosis calcification Lungs Bronchopneumonia, abscesses, intraalveolar edema, fibrin deposition, hyaline membranes, foreign body

giant cell reaction to food material or keratinaceous debris (aspiration) Radiation pneumonitis (diffuse alveolar damage, organizing pneumonia, interstitial and alveolar fibrosis, vascular intimal fibrosis with foamy macrophages) Thromboemboli intraalveolar hemorrhage Cardiovascular Subendocardial/myocardial contraction band injury, coagulative necrosis, edema, hemorrhage neutrophils, macrophages Kidneys Acute tubular injury/necrosis: Dilated tubules, epithelial cell sloughing/necrosis, pigmented tubular casts Liver Shock changes: Centrilobular (perivenular) congestion hepatocellular necrosis without significant inflammation Sepsis changes: Canalicular cholestasis, bile ductular cholestasis associated neutrophils Brain Parenchymal infarcts: Vacuolization of white matter, shrunken red neurons (eosinophilic cytoplasm, pyknotic nuclei) neutrophils, macrophages, hemorrhage

ANCILLARY TESTS Microbiology

Postmortem blood, wound, tissue/fluid cultures can be performed if not done premortem

REPORTING CONSIDERATIONS Final Report Should Include

Immediate cause of death and how it relates to surgery Other postsurgical complications Risk factors for developing postsurgical complications Presence of residual/metastatic disease

SELECTED REFERENCES 1.

2. 3. 4.

Kim KM et al: Major early complications following open, laparoscopic and robotic gastrectomy. Br J Surg. 99(12):1681-7, 2012 Raymond D: Complications of esophagectomy. Surg Clin North Am. 92(5):1299-313, 2012 Schieman C et al: Patterns of operative mortality following esophagectomy. Dis Esophagus. 25(7):645-51, 2012 Smith JK et al: National outcomes after gastric resection for neoplasm. Arch Surg. 2007 Apr;142(4):387-93. Erratum in: Arch Surg. 144(7):634, 2009 Atkins BZ et al: Reducing hospital morbidity and mortality following esophagectomy. Ann Thorac Surg. 78(4):1170-6; discussion 1170-6, 2004 Wang CS et al: Resectable gastric cancer: operative mortality and survival analysis. Chang Gung Med J. 25(4):216-27, 2002 Karl RC et al: Factors affecting morbidity, mortality, and survival in patients undergoing Ivor Lewis esophagogastrectomy. Ann Surg. 231(5):635-43, 2000

Gross and Microscopic Findings (Left) Radiation pneumonitis in a patient who was irradiated for esophageal carcinoma is characterized by features of diffuse alveolar damage with intraalveolar fibrin and inflammation as well as fibroblastic foci with reactive atypia of pneumocytes and fibroblasts . (Right) Chylothorax is a rare complication of esophagectomy, characterized by a turbid, milky, yellow-white effusion and occurs as a result of thoracic duct injury. (Courtesy R. Irvine, MD.)

(Left) The proximal stomach is connected directly to the duodenum in the Billroth I anastomosis and is connected to the jejunum with closure of the proximal duodenum in the Billroth II anastomosis after partial gastrectomy. (Right) The esophagus or proximal stomach is connected to a portion of divided jejunum , and the other end of the proximal jejunum is reconnected to the distal jejunum , creating a "Y" shape in the Roux-en-Y anastomosis after gastrectomy.

(Left) Gastric remnant adenocarcinoma composed of poorly formed tubules with numerous tumorinfiltrating lymphocytes (gastric carcinoma with lymphoid stroma) was present near the gastroenteric anastomosis in a patient status post partial gastrectomy 40 years prior for peptic ulcer disease. (Right) In situ hybridization for EBV (EBER) is positive (red) in tumor cell nuclei and negative in lymphocytes in this EBV-associated gastric remnant carcinoma with lymphoid stroma.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

GASTRECTOMY AND ESOPHAGECTOMY

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

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BARIATRIC SURGERY

This residual sleeve of stomach shows mucosal necrosis along the staple line with associated dehiscence and leak, status post laparoscopic sleeve gastrectomy. (Courtesy R. Irvine, MD.)

TERMINOLOGY Definitions

Morbid obesity: Body mass index (BMI) 40 kg/m or

Peritonitis characterized by a greenish exudate covering the peritoneal and abdominal organ serosal surfaces was due to a leak status post laparoscopic sleeve gastrectomy.

Modification: Duodenal switch procedure: Vertical sleeve gastrectomy (in lieu of partial distal gastrectomy for preservation of antrum and pylorus) combined with duodenoenterostomy

BMI 35 kg/m with associated comorbidities

Types of bariatric surgery: Restrictive vs. both

restrictive and malabsorptive Restrictive procedures Gastric banding Laparoscopic adjustable gastric banding: Band wrapped around entire stomach to create pouch; adjustable and reversible; continuity of gastrointestinal tract remains intact Vertical banded gastroplasty: Gastric pouch and "window" (defect through both anterior and posterior walls) created with staples; band wraps around pouch through window to restrict pouch Laparoscopic sleeve gastrectomy: Vertical resection of lateral portion (~ 80%) of stomach to create thin residual "sleeve" Restrictive and malabsorptive procedures Roux-en-Y gastric bypass Stomach is divided proximally to create a small pouch, which is connected directly to a segment of jejunum (Roux limb) Remaining bypassed stomach with attached duodenum and proximal jejunum is stapled closed proximally Jejunojejunostomy creates "Y" intersection Biliopancreatic diversion: Not commonly performed Partial distal gastrectomy and closure of duodenal stump Small bowel divided between ligament of Treitz and ileocecal valve with Roux-en-Y gastroenterostomy of proximal gastric pouch to distal portion of small bowel Biliopancreatic limb (duodenum and proximal small bowel) anastomosed to distal small bowel

CLINICAL ISSUES Epidemiology Incidence

Incidence of morbid obesity in USA: 2-5% Incidence of complications of bariatric surgery: Up to 20% depending on procedure; average: 6-10%

Presentation

Symptoms: Abdominal pain, nausea, vomiting, dysphagia, hematemesis, melena, chest pain, dyspnea

Signs: Tachycardia, tachypnea, arrhythmia, hypotension, altered mental status

Important elements of chart review

Underlying comorbidities: Diabetes mellitus, coronary artery disease, hypertension, obstructive sleep apnea, obesity hypoventilation syndrome, cirrhosis, dyslipidemia, cholelithiasis Type of operation performed, intraoperative complications, postoperative course, interventions performed for complications, concurrent surgical procedures (e.g., herniorrhaphy, cholecystectomy)

Laboratory Tests

Leukocytosis, lactic acidosis, blood urea nitrogen and creatinine (sepsis)

C-reactive protein, lactate, and B-type natriuretic peptide (BNP)

hemoglobin and hematocrit, (+) fecal occult blood, (+) D-dimer

serum iron, ferritin, transferrin saturation, and reticulocyte count; total iron binding capacity (iron deficiency)

Key Facts Terminology

Types of bariatric surgery: Gastric banding (vertical banded gastroplasty vs. laparoscopic adjustable gastric banding), laparoscopic sleeve gastrectomy, Roux-en-Y gastric bypass, biliopancreatic diversion

Clinical Issues

Incidence of morbid obesity in USA: 2-5% Incidence of complications of bariatric surgery: Up to 20% depending on procedure; average 6-10%

Risk factors for complications: Male sex, older age, higher preoperative BMI, diabetes mellitus, pulmonary hypertension, low hospital case load, prolonged operation time, open surgery Overall mortality: ~ 0.05-5% Common causes of death: Pulmonary embolism, sepsis, arrhythmia, hemorrhage

Megaloblastic anemia (B12 and folate deficiency), microcytic hypochromic anemia (iron deficiency)

(+) blood, wound, fluid collection (e.g., abscesses, ascites, effusions) cultures

Prognosis

Overall mortality: ~ 0.05-5% Mortality rate by procedure: Banding < sleeve gastrectomy < Roux-en-Y bypass < biliopancreatic diversion Common causes of death: Pulmonary embolism, sepsis, arrhythmia, hemorrhage

Complications

Risk factors for complications

Male sex, older age, higher preoperative BMI, diabetes mellitus, pulmonary hypertension Low hospital case load, prolonged operative time, open vs. laparoscopic surgery Early complications Deep vein thrombosis (DVT), pulmonary embolism, gastrointestinal ulcers/hemorrhage/ischemia, small bowel obstruction, adhesions, fistulas, strictures, arrhythmia Sepsis due to wound infection, anastomotic leak/ dehiscence, intraabdominal abscess Hemorrhagic shock due to iatrogenic vascular injury, pseudoaneurysms Complications related to band: Pressure necrosis of stomach, erosions, reflux, band/port infection, band slippage/migration, tube or port disconnection

small bowel obstruction, perforation Late complications Vitamin deficiencies: Folate, iron, B12, fat-soluble vitamins Protein-calorie malnutrition Adhesions/strictures obstruction Reflux esophagitis Barrett esophagus dysplasia/ adenocarcinoma

Early complications

Deep vein thrombosis, pulmonary embolism, gastrointestinal ulcers/hemorrhage/ischemia, small bowel obstruction, adhesions, fistulas, strictures, arrhythmia Sepsis due to wound infection, anastomotic leak/ dehiscence, intraabdominal abscess Hemorrhagic shock due to iatrogenic vascular injury, pseudoaneurysms Complications related to band

Macroscopic Pathology

Evaluate upper gastrointestinal tract in situ for fistulas and anastomotic leaks

Note location and status of band, if present Remove esophagus, stomach, and small bowel (if part of anastomosis) en bloc, then open

IMAGE FINDINGS Ultrasonographic Findings Duplex ultrasound for DVT

CT Findings

Ascites, intraabdominal abscess, abdominal free air, intestinal obstruction, pleural/pericardial effusions, pulmonary infiltrates CT pulmonary angiography for pulmonary embolism

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

BARIATRIC SURGERY

Upper GI Series/Contrast Swallow

Anastomotic leaks, strictures, ulcers, evidence of band dislocation/slippage

CT Angiogram

Identify/treat active bleeding, vascular injury, pseudoaneurysms, fistulas

MACROSCOPIC FEATURES External Examination

Surgery-related: Wound status, drains, incisional hernias, cutaneous fistulas

Obesity-related: weight (record weight and height to calculate BMI at postmortem), decubitus ulcers, venous stasis, striae, excess skin folds after significant weight loss Sepsis changes: Petechiae, jaundice, acrocyanosis Shock changes: Pallor (also related to anemia)

Internal Examination

Ascites, peritonitis (green fibrinous exudates on peritoneal/serosal surfaces), hemoperitoneum

Organ Examination

Evaluate upper gastrointestinal tract in situ for surgically altered anatomy, fistulas, and anastomotic/ staple line leaks May perfuse esophagus with water or dye to assess for leaks

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

BARIATRIC SURGERY Note location and status of band and associated connecting tube and port, if present Remove esophagus, stomach, and small bowel (if part of anastomosis) en bloc Esophagus: Mucosal erythema, erosions, tan/ salmon-colored mucosa (Barrett esophagus) Stomach: Mucosal erosions/ulcers, anastomotic ulcers/dehiscence perforation, perigastric abscesses, fistulas Small and large intestine: Obstruction, strictures, fistulas, adhesions, perforations, ischemic changes (dusky red-black mucosa ulcers, tan-green pseudomembranes), thrombi in mesenteric vessels Obesity-related findings Atheromas in pulmonary arteries (pulmonary hypertension) Cardiomegaly, biventricular hypertrophy and dilatation (obesity cardiomyopathy) Right ventricular hypertrophy and dilatation (cor pulmonale: May relate to associated obstructive sleep apnea), concentric left ventricular hypertrophy (hypertension), atrial dilatation Hepatomegaly, yellow fatty cut surface (obesityrelated metabolic syndrome), cirrhosis (due to nonalcoholic fatty liver disease) Cholelithiasis (obesity risk) Surgery-related findings Pulmonary thromboemboli, wedge-shaped hemorrhagic infarct, fibrinous pleural exudate, consolidation/congestion Evidence of vascular injury/pseudoaneurysms Legs can be "milked" for DVT once organs are removed Shock/sepsis changes Subendocardial/myocardial mottling, tan-yellow soft areas hyperemic borders (if sepsis or hemorrhagic complications have caused myocardial ischemia) Liver: Congestion and necrosis (shock), cholestasis (sepsis) Kidneys: Cortical pallor, medullary congestion (shock)

MICROSCOPIC PATHOLOGY Histologic Features Gastrointestinal tract

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Anastomotic ulcers, transmural inflammation necrosis, acute/organizing serositis, fibroinflammatory adhesions Ischemic enterocolitis: Epithelial necrosis/sloughing, mucosal ulcers, hemorrhage, transmural necrosis, remaining crypts are "withered," mucopurulent exudate (pseudomembranes) mesenteric arterial thrombi, atherosclerosis Reflux esophagitis, Barrett esophagus dysplasia

adenocarcinoma Obesity-related findings Pulmonary vessels with medial hypertrophy, intimal hyperplasia/fibrosis, plexiform arteriopathy with

capillary tufts forming web that spans lumen (pulmonary hypertension) Fat within right ventricle without fibrosis, myocyte hypertrophy (obesity cardiomyopathy) Hepatic steatosis, steatohepatitis fibrosis, cirrhosis Cholecystitis, cholesterolosis Renal diabetic or hypertensive changes ( risk with obesity) Surgery-related findings Pulmonary artery thromboemboli recanalization, intraalveolar hemorrhage Shock/sepsis changes Bronchopneumonia, abscesses, intraalveolar edema, or alveolar hyaline membranes with edema and inflammation (i.e., diffuse alveolar damage) Subendocardial/myocardial contraction band injury, coagulative necrosis, edema, hemorrhage neutrophils, interstitial fibrosis/scar Canalicular, hepatocellular, and ductular cholestasis (sepsis) Centrilobular congestion hepatocellular necrosis (shock) Dilated renal tubules, epithelial sloughing (i.e., acute tubular injury/necrosis)

ANCILLARY TESTS Microbiology

Postmortem blood, wound, fluid collection, and tissue cultures if not done premortem

REPORTING CRITERIA Final Report Should Include

Immediate cause of death and how it relates to surgery Other postsurgical complications Risk factors for developing complications

SELECTED REFERENCES 1.

2. 3.

Benotti P et al: Risk factors associated with mortality after Roux-en-Y gastric bypass surgery. Ann Surg. 259(1):123-30, 2014 Fryer E et al: Postmortem examination in the morbidly obese. Histopathology. 64(2):200-10, 2014 Anderson B et al: Biliopancreatic diversion: the effectiveness of duodenal switch and its limitations. Gastroenterol Res Pract. 2013:974762, 2013 de la Matta-Mart n M et al: Perioperative morbi-mortality associated with bariatric surgery: from systematic biliopancreatic diversion to a tailored laparoscopic gastric bypass or sleeve gastrectomy approach. Obes Surg. 22(7):1001-7, 2012 Kirshtein B et al: Bariatric emergencies for non-bariatric surgeons: complications of laparoscopic gastric banding. Obes Surg. 20(11):1468-78, 2010 Cummings PM et al: Postmortem findings in morbidly obese individuals dying after gastric bypass procedures. Hum Pathol. 38(4):593-7, 2007

Gross and Microscopic Features (Left) A band is wrapped around the proximal stomach to create a small pouch in the laparoscopic adjustable gastric banding procedure. A connecting tube attaches to a port to inflate/deflate band. (Right) A small pouch of stomach is connected to a segment of jejunum (Roux limb) , and the remaining portion of stomach with duodenum and proximal jejunum is closed proximally . A jejunojejunostomy creates the "Y" intersection in a Roux-en-Y gastric bypass.

(Left) A saddle embolus in the pulmonary artery bifurcation was the cause of death status post Roux-en-Y gastric bypass surgery. (Right) Sections through the lung in a patient with pulmonary embolism after gastric bypass surgery show organizing thromboemboli in the arteries with associated vascular congestion .

(Left) The anterior abdominal wall contained a mesh with purulent exudate in a patient with a chronically infected incisional herniorrhaphy wound, status post open gastric bypass surgery. Loops of small bowel were entrapped in adhesions around the mesh. (Courtesy M. Nagar, MD.) (Right) The remnant (excluded) stomach showed ischemic mucosal necrosis with vascular congestion as a result of adhesions to the reduced gastric pouch in the same patient.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

BARIATRIC SURGERY

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CENTRAL NERVOUS SYSTEM TUMORS

A young adult died with a pilocytic astrocytoma (WHO grade I) in the hypothalamus . There was local infiltration into the mammillary bodies , which are becoming obscured, and into the optic chiasm.

TERMINOLOGY Scope

Brain tumors in adults, including incidental, 1st discovered at autopsy, or post-therapy settings

ETIOLOGY/PATHOGENESIS Familial

5%, most syndromic Neurofibromatosis type 1 and type 2, Li-Fraumeni, von Hippel-Lindau, and Turcot syndromes

Nonsyndromic

Tend to be high grade Usually few cases in consecutive generations Low risk of more family members developing glioma

Sporadic

No clear causative associations

Post Radiation Tumors Meningiomas Parenchymal gliomas

Metastatic Brain Tumors

Lung, breast, skin (melanoma), kidney, colon

CLINICAL ISSUES Epidemiology

Diffusely infiltrating astrocytomas (> 60% of primary

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brain tumors) Diffuse astrocytoma (WHO grade II) Anaplastic astrocytoma (WHO grade III) Glioblastoma (WHO grade IV) > 50% of all astrocytomas Meningiomas ~ 30% of intracranial tumors

A low-grade infiltrating glioma is seen in the left frontal lobe . A previously well young man with sudden malaise lost consciousness and fell to his death. Autopsy revealed a large oligodendroglioma (WHO grade II).

Metastatic brain tumors 14-22%

Presentation

Headache, nausea/vomiting, behavior change, fatigue, seizure, hemorrhage

Natural History

Local effects and progression

Infiltration, pressure on vital brain centers Fatal pressure on brainstem, upper spinal cord Intratumoral hemorrhage; massive can be fatal Intracranial and occasionally spinal dissemination Cause of death (gliomas) Low-grade gliomas Progression to high-grade glioma, involvement of brainstem, death from other illnesses High-grade gliomas; often multifactorial Herniation (subfalcial, transtentorial, tonsillar) Death in postoperative period Severe systemic illness (coagulopathy/pulmonary embolus, myocardial infarct, infection/sepsis) Sudden death (true sudden death rare) 3rd ventricle colloid cyst at foramina of Monro High-grade astrocytoma, oligodendroglioma

Treatment

Resection, steroids, radiation, chemotherapy Complications Immunosuppression Infections Bacterial Viral

MACROSCOPIC FEATURES Surgical Sites

Inspect surgical incision site(s)

Key Facts Clinical Issues

Diffusely infiltrating astrocytomas (> 60% of primary brain tumors) Glioblastoma (grade IV); > 50% of astrocytomas Local effects and progression Infiltration, pressure on vital brain centers Fatal pressure on brainstem, upper spinal cord Intracranial and occasionally spinal dissemination Cause of death: Low-grade glioma Progression to high-grade glioma, brainstem involvement, death from other illnesses Cause of death: High-grade glioma Herniation (subfalcial, transtentorial, tonsillar) Death in postoperative period Severe systemic illness (coagulopathy/pulmonary embolus, myocardial infarct, infection/sepsis)

State of wound closure: Inflamed, purulent, healed, sutures, staples Ventricular drainage tubes: Number, location Operative site, including hemorrhage, herniation Fungus cerebri: Swollen brain protruding through craniotomy site

Calvarial and Brain Examination

Calvaria: Modify calvarial removal as required (e.g., posthemicraniectomy) Dura: Surgical site, grafts, neomembrane, tumor attachment Brain: Generally no modification to routine removal and sectioning

Glioma

Low grade (WHO I-II)

Solid (diffuse glioma), or cystic (pilocytic astrocytoma); homogeneous Possible subtle effacement, obscuring gray-white junction (not well demarcated) High grade (WHO III-IV) Solid (anaplastic glioma, many glioblastomas) or cystic (glioblastoma), heterogeneous, variegated (gray-white, yellow or tan necrosis/hemorrhage) Thick infiltrated corpus callosum and fornix Spread to opposite hemisphere ("butterfly glioma") Invaded ventricular space, local dural attachment

Ependymoma

Soft, well demarcated, associated with ventricles

Meningioma

Firm, lobulated, dural based

Metastatic Tumors

Single or multiple masses (small or large) Usually develop at gray-white junction

Massive intratumoral hemorrhage Sudden death 3rd ventricle colloid cyst at foramina of Monro High-grade gliomas

Reporting Considerations

Correlation with clinical reports

Extent of tumor, including further tumor spread Histology consistent with radiation necrosis Associated conditions and complications Herniations, secondary hemorrhage Hypoxic changes, infarcts Familial tumor: Syndromic, non-syndromic Radiation-induced tumor Unexpected tumor, incidental to cause of death Meningioma(s), colloid cyst of 3rd ventricle, subependymoma, hamartoma, lipoma

Tumor-Associated Findings

Midline shift Herniation: Subfalcial, uncal, tonsillar 2 occipital infarct, brainstem hemorrhage

MICROSCOPIC PATHOLOGY Histologic Features Glioma

Astrocytic, oligodendroglial, mixed High-grade (anaplastic) features Hypercellularity, pleomorphism Mitoses 6/10 HPF Vascular endothelial hyperplasia Necrosis Meningioma Majority are WHO grade I: Typical meningioma Atypical meningioma (WHO II): Necrosis, small-cell appearance, prominent nucleoli, loss of lobularity (3 of 4 required); or mitoses 4/10 HPF alone; or brain invasion alone Anaplastic meningioma (WHO III): Mitoses 20/10 HPF; usually necrosis and marked pleomorphism Metastasis Morphology, immunohistochemistry History to suggest primary Autopsy examination of other organs Radiation necrosis Vessel wall hyaline thickening, fibrinoid necrosis, endothelial proliferation, thrombosis Extravasated fibrin, telangiectases, necrosis, gliosis, calcifications

SELECTED REFERENCES 1.

Therapy-Related Changes

Extensive necrotic or little visible tumor, hemorrhage

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CENTRAL NERVOUS SYSTEM TUMORS

Brat D, et al: Protocol for the Examination of Specimens From Patients With Tumors of the Brain/Spinal Cord. Northfield: College of American Pathologists. 2013 Louis D et al: WHO Classification of Tumours of the Central Nervous System. Geneva: WHO Press, World Health Organization. 2007

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CENTRAL NERVOUS SYSTEM TUMORS

Gross Brain Tumor Features (Left) This coronal section of the cerebral hemispheres shows the classic appearance of a glioblastoma with central necrosis extending to the splenium of the corpus callosum . (Right) A glioblastoma in the left frontal lobe thickens and obscures the body of the corpus callosum . The tumor crosses to the right frontal lobe . This appearance is termed "butterfly glioma." The columns of the fornix are also infiltrated. A left cingulate gyrus (subfalcial) herniation under the falx is present.

(Left) A glioblastoma with massive postoperative hemorrhage herniated through the surgical site of the skull (fungus cerebri) , seen externally and in axial section. Decompressive hemicraniectomy prevents this disastrous complication of surgery for tumor, infarct, or other significant lesion causing an expanding brain. (Right) There is a large postoperative subfalcial herniation . The operative site for this highgrade glioma and the area over the body of the corpus callosum show substantial hemorrhage.

(Left) This left frontal lobe glioblastoma caused a midline shift and cingulate herniation . An uncal herniation (not see here) compressed the left posterior cerebral artery leading to a secondary medial occipital lobe hemorrhagic infarct . (Right) Uncal herniation from the tumor itself or from a complication such as a large hemorrhage can push the brainstem caudally, pulling on blood vessels and causing this mostly midline secondary brainstem hemorrhage of the midbrain and pons .

Gross and Microscopic Brain Tumor Features (Left) A brainstem glioblastoma encircles the basilar artery by exophytic tumor growing anteriorly from the pons. Rostral basilar artery is seen . Pons is expanded . Tumor also infiltrates the medulla , which is widened. (Right) The dural cap was removed from this left frontoparietal meningioma (WHO grade I) . The tumor’s growth over a long period of time depressed the dorsolateral brain tissue so that when the tumor was removed, a large defect was found. No brain infiltration had occurred.

(Left) This dura-based (falx cerebri) meningioma (WHO grade I) was biopsied or partially resected 35 years previously. The actual remote procedure was not available at autopsy. The patient died of longstanding cardiac disease. (Right) A meningioma (WHO grade I) causes devastating brainstem compression in this axial section. The pons is compressed and deviated to the right by the meningioma. Pontine compression can cause cardiorespiratory compromise.

(Left) Multiple metastases of a pulmonary adenocarcinoma are at or near the gray-white junction . One neocortical metastasis is hemorrhagic , and another metastatic deposit is in white matter . Large, confluent metastases expand the area of the right thalamus . (Right) A pilocytic astrocytoma (WHO grade I) is biphasic, with compact and loose regions required for diagnosis. Pilocytic tumor cells (hairlike) are thin and elongated with small nuclei .

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CENTRAL NERVOUS SYSTEM TUMORS

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CENTRAL NERVOUS SYSTEM TUMORS

Microscopic Brain Tumor Features (Left) Pilocytic astrocytomas usually have brightly eosinophilic Rosenthal fibers in compact regions. Rosenthal fibers, although not required or specific, are characteristic of childhood and adult pilocytic astrocytomas. (Right) This is a diffuse fibrillary astrocytoma (WHO grade II) of the lower medulla and upper cervical spinal cord (cervicomedullary lowgrade tumor). The elongated astrocytoma cells resemble normal fibrillary astrocytes . There are no compact regions.

(Left) Anaplastic astrocytoma (WHO grade III) is more pleomorphic than the fibrillary astrocytoma. Vascular endothelial hyperplasia is a high-grade feature. (Right) Glioblastoma (WHO grade IV) usually has at least some enlarged astrocytic tumor cells in routine stains, but glioblastoma cells may be mostly poorly differentiated. There is both vascular endothelial hyperplasia, seen here as a glomeruloid vascular structure with multiple small lumina containing red cells and at least focal necrosis (not seen here).

(Left) Glioblastomas may have a crowded layer of (pseudopalisading) cells around necrosis, with the crowded tumor cells presumably migrating from the central anoxic area (center of necrosis often contains a thrombosed microvessel). (Right) Oligodendroglioma (WHO grade II) cells have optically empty cytoplasm (fried egg or honeycomb appearance) and delicate capillaries. Cytoplasmic clearing is an artifact of delayed fixation. Nuclei are mostly round but some are oval.

Microscopic Brain Tumor Features (Left) Anaplastic oligoastrocytoma (WHO grade III) has oligodendroglioma and astrocytoma cells , with a high mitotic rate &/or vascular endothelial hyperplasia. (Right) Meningiomas have spindle cells and are dural based. Most are WHO grade I (seen here), with cells in small or large fascicles, and lobules of syncytial-appearing and whorled cells may be seen. Psammoma bodies are characteristic.

(Left) Small, tight, cellular whorls are often seen in meningiomas. Psammoma bodies may be small or large. (Right) This desmosometype junctional complex with tonofilaments extending from it aids in meningioma diagnosis. The differential diagnosis of an intracranial spindle cell tumor is schwannoma, which lacks junctional complexes but has basement membranes. Meningiomas do not have basement membranes around their cells.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CENTRAL NERVOUS SYSTEM TUMORS

(Left) Metastatic adenocarcinoma has a "pushing" margin at the brain interface . Perivascular infiltration is also typical. (Right) Radiation necrosis in this patient with a treated glioblastoma manifests as necrosis , vascular wall thickening , fibrin , and vascular exudation fibrinoid necrosis . Old hemorrhage in the tissue is evidenced by hemosiderin pigment .

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CEREBRAL ANEURYSM AND VASCULAR MALFORMATION

Subarachnoid hemorrhage around the sylvian fissure suggests the location of the ruptured right middle cerebral artery aneurysm. Some subarachnoid blood has also settled over the brainstem .

TERMINOLOGY Abbreviations

Arteriovenous malformation (AVM)

ETIOLOGY/PATHOGENESIS Developmental Aneurysms

Saccular, "berry," or congenital (although rarely present at birth) aneurysms

Lacks medial smooth muscle layer, precluding formation of internal elastic lamina Internal elastic lamina provides tensile strength Systolic blood pressure enlarges wall over time into saccular aneurysm Usually at bifurcations (circle of Willis) Distal aneurysms (not at bifurcation) mostly cerebellar AVM-associated aneurysms ( hemodynamic instability): Alter prognosis, management

Acquired Aneurysms

Vascular wall damage, repair

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Trauma (pseudoaneurysm): Often near dural free edge AVM-associated acquired aneurysms Spheroidal (early) or fusiform (late alteration) Intrinsic vascular wall weakness Genetic predisposition Vascular Ehlers-Danlos syndrome Sickle cell anemia Vertebrobasilar dolichoectasia (arteriopathy) Mostly older males; hypertension association Juvenile cases (rare) Connective tissue disorders, sickle cell disease Mycotic (infective) aneurysms Usually 2 to bacterial endocarditis Fungal infection (very rare)

A ruptured anterior communicating artery aneurysm is seen on the circle of Willis, with arachnoidal tissue dissected away. The middle cerebral arteries and basilar artery are indicated.

Vascular Malformations Blood vessel hamartomas Most cases sporadic

Genetic background; some cases

Osler-Weber-Rendu disease Sturge-Weber disease AVM Arterial feeder systolic pressure directly enters abnormal veins Affected vessels leak blood pigment, gliosis Rupture not inevitable but may be fatal Cavernous angioma Focally thin walls in large abnormal vessels may rupture Capillary hemangioma Usually incidental finding Telangiectasia (telangiectases) 4-12% of vascular malformations Venous malformation Frequent, usually incidental finding Low pressure, rupture infrequently Vein of Galen aneurysmal malformation Infrequent; may cause high-output cardiac failure Dural arteriovenous fistula or shunt Direct connection between dural artery and brain/ spinal cord blood vessels Leak or sudden rupture into neural parenchyma Foix-Alajouanine syndrome or venous congestive myelopathy Reflux of dural arterial blood into spinal cord venous drainage

CLINICAL ISSUES Presentation

Developmental (saccular) aneurysms Autopsy prevalence rate 1-5% Annual rupture rate < 2%

Key Facts Etiology

Developmental aneurysms

Termed saccular, "berry," or congenital aneurysms (rarely appear at birth) Lacks medial smooth muscle layer, precluding formation of internal elastic lamina Vertebrobasilar dolichoectasia (arteriopathy) Focally dilated basilar artery, mostly older men Longstanding case may form fusiform aneurysm Vascular malformations AVM: No capillary bed; may cause seizures, prone to rupture Cavernous angioma, prone to rupture Capillary hemangioma Telangiectasia (telangiectases) Venous malformation, minor to extensive

Up to 80% do not rupture (incidental) Can be incidental on imaging report for other investigations Subarachnoid hemorrhage (major presentation) Headache, mental status change, neck stiffness, focal neurologic deficits, acute brain injury Subdural hematoma (rare) Distal embolization (rare) Acquired aneurysms Infrequent, may be 2 to larger problem (e.g., connective tissue disorder) Vertebrobasilar dolichoectasia 10% symptomatic Brain ischemia, cranial nerve or brainstem compression, cerebellar symptoms, obstructive hydrocephalus, fatal rupture AVM Prevalence: 18/100,000 adults Autopsy prevalence rate: 1-4% Clinical imaging incidental rate: 0.05% Lifetime bleeding risk: 17-90% Depends on size, location (e.g., deep), venous drainage, associated aneurysm, previous bleed Presentation with rupture Hemorrhage (50%) Seizure (25%) Headache (25%) Focal neurologic deficits Unruptured (present 2x as commonly as ruptured) 1st hemorrhage fatality rate: 15-18% After 1st rupture, 4-34% rerupture risk: Higher for deep brain location or deep venous drainage Overall morbidity/mortality estimates uncertain Associated developmental or acquired aneurysm in 3-16% Worse prognosis if large or eloquent area (brainstem, thalamus, hypothalamus, motor or sensory [parietal, visual] cortex) Better prognosis for small AVM ( 3 cm) Angiographically occult AVM: < 3 cm or thrombosed Annual bleeding risk: < 1%

Dural arteriovenous fistula or shunt; potential for major clinical hemorrhage

Clinical Issues

Subarachnoid or intraparenchymal hemorrhage, seizure disorder, fatal rupture

Medical treatment (antiepileptics), open surgery, endovascular thrombosis-promoting procedures

Macroscopic Pathology

Aneurysm rupture often obscured by blood; multiple aneurysms common

Common incidental finding (aneurysm, vascular malformation)

Microscopic Pathology

Developmental aneurysmal wall characteristic Malformed vessels in AVM Cavernous angioma

Subarachnoid/intraparenchymal bleed with rupture

Capillary hemangioma

Symptoms if size increase tissue pressure

Telangiectases and venous malformations Commonly incidental

Dural arteriovenous fistula or shunt

Leak or sudden rupture into neural parenchyma

Treatment

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CEREBRAL ANEURYSM AND VASCULAR MALFORMATION

Surgical approaches

AVM or cavernous angioma extent &/or vascular supply may limit or prevent surgical approach Aneurysm Small (< 7 mm) aneurysms: Small rupture potential, traditionally observed, but increasingly embolized Surgical clipping (open): Larger aneurysms Endovascular embolization (coils, stent-assisted coils, pipeline embolization mesh) AVM Staged multimodality, for vessel obliteration Stereotactic (focused) irradiation (radiosurgery) Endovascular embolization (polymer, glue) Excision; may follow radiation, embolization Observation: Active treatment harm if unruptured; case dependent Brainstem AVM: Single-mode less harmful

Prognosis

Developmental aneurysms

Subarachnoid hemorrhage Mortality rate 45%; most deaths in 1st week Reduced mortality (13-35%) in centers with higher case numbers Rebleed untreated or treated mortality rate Morbidity/mortality factors Acute brain injury: Vasospasm, hypoxia, infarcts Rebleed risk: Older patient, size > 10 mm, blood pressure > 160 mm Hg, poor initial clinical status Morbidity/mortality rate after endovascular coiling lower than after surgical clipping

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CEREBRAL ANEURYSM AND VASCULAR MALFORMATION Coil-packed ruptured aneurysm rebleed rate ~ 1% higher compared to clipping Complications: Seizures, SIADH, hydrocephalus Cause of death Subarachnoid hemorrhage sequelae (acute brain injury) Treatment complications in 1st postoperative year Pneumonia, organ failure (cardiopulmonary) Intracerebral hemorrhage (rare) AVM Associated aneurysm(s) prognosis Unruptured with associated aneurysm: 7% annual hemorrhage risk Hemorrhage risk over time Radiation rebleed risk for large AVM Embolization alone hemorrhage risk for 1 year Brainstem AVM prognosis favorable Seizure risk same with drugs or surgery Combined therapy compounds treatment-related risk Hemorrhage risk until full obliteration (many years) Cause of death Intracerebral hemorrhage, herniation Treatment complications, seizures Operative complication

Pertinent Antemortem Data

CBC, PT, aPTT Computed tomography (CT), reconstructed computed tomography angiogram (CTA)

Magnetic resonance imaging (MRI) Conventional angiography Operative and radiation therapy report(s)

MACROSCOPIC FEATURES Aneurysm

Incidental in some autopsies, usually circle of Willis May be multiple, occasionally symmetrical

Rupture with subarachnoid hemorrhage

Clip, coils, stent, mesh visible or palpable, if used Blood often obscures aneurysm Aneurysm usually at epicenter of hemorrhage Dissect away blood and cerebral tissue as needed May require multiple samples from hemorrhage to locate aneurysm microscopically With no organ retention permitted, remove some blood and fix area(s) likely to contain aneurysm Postmortem cerebral angiography for location (brain edema may interfere by vascular collapse)

Variable appearance Residual vessels often grossly apparent Embolized polymer in AVM, may migrate past malformed vessels

MICROSCOPIC PATHOLOGY Histologic Features Aneurysm

Fraying and loss of internal elastic lamina at aneurysm neck Collagenous tissue in sac wall, no smooth muscle Rupture site, if seen, often in sac dome Fragile fibrin plug (rarely found) Dolichoectasia Smooth muscle atrophy, fragmented internal elastic lamina Vascular malformations Back-to-back vessel walls in part or entirely Wall thickness from capillary-like to very thick Types prone to rupture have arterial feeder &/or some thin vessel walls AVM No capillary bed; intervening parenchyma present Old blood pigment, calcification/bone, gliosis Cavernous angioma Large abnormal vessels, no intervening parenchyma Old blood pigment, gliosis Capillary hemangioma Small thin-walled vessels, little if any intervening parenchyma Telangiectasia Loosely clustered or scattered very thin-walled, dilated branches Wall: Endothelium, some pericytes Venous malformation Variable; very thin vessel walls (focally endothelium and little adventitia) to very thick Rare: 1 anomalous vein Dural arteriovenous fistula or shunt Enlarged arterialized subarachnoid veins, thickened elastic laminae Venous congestive myelopathy: Enlarged subarachnoid veins and small, dilated, thickwalled spinal cord vessels; spinal cord congestion and hemorrhage, gray matter necrosis

SELECTED REFERENCES 1.

Vascular Malformation

Common incidental finding

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Usually venous anomaly or telangiectasia Occasionally, only old blood pigment or vague discoloration grossly Inoperable AVM or cavernous angioma Often large; in brainstem, may be small Often at least a few vessels over 1 mm in diameter Old blood pigment, firm surrounding gliosis Post-treatment lesion

Bradac O et al: Treatment for brain arteriovenous malformation in the 1998-2011 period and review of the literature. Acta Neurochir (Wien). 155(2):199-209, 2013 Karamanakos PN et al: Risk factors for three phases of 12-month mortality in 1657 patients from a defined population after acute aneurysmal subarachnoid hemorrhage. World Neurosurg. 78(6):631-9, 2012 McNulty ML et al: Management of unruptured intracranial aneurysms and arteriovenous malformations. Am J Ther. 18(1):64-9, 2011 Love S et al: Greenfield’s Neuropathology. 8th ed., vol. 1. London: Edward Arnold, 2008

Gross and Angiographic Features (Left) Subarachnoid hemorrhage covers a ruptured distal aneurysm of the left posterior inferior cerebellar artery. An infarct in the medulla causes the Wallenberg syndrome. (Right) Basilar artery dolichoectasia pushed the basis pontis laterally . These spheroidal dilations become fusiform later. They can cause cardiorespiratory failure from pontine compression. Dolichoectasia ("long dilated") has hypertension, trauma, genetic, and AVM associations.

(Left) Onyx injected into the feeding artery of a large frontoparietal AVM has high attenuation so that its distribution is clearly seen in this cerebral angiogram. (Right) Onyx, a viscous black polymer mixture, fills all vascular sizes in this cerebral AVM photographed in the surgical suite after excision. The dark, somewhat firm polymer is seen through the relatively thin (for size) abnormal vascular walls . (Courtesy G. Gupta, MD.)

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CEREBRAL ANEURYSM AND VASCULAR MALFORMATION

(Left) A patient with a chronic seizure disorder had an AVM of the right occipital lobe . No surgical procedure was performed on it, but a seizure was thought to have contributed to death. (Right) This patient with a chronic seizure disorder had a right medial frontal orbital AVM. Several abnormal vessels are large and easily seen . Blood leakage and perhaps small ruptures resulted in a cavity in the white matter with blood-stained walls .

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Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

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CEREBRAL ANEURYSM AND VASCULAR MALFORMATION

Gross, Angiographic, and Microscopic Features (Left) Very wide-bore, back-toback venous structures make up this extensive, inoperable cavernous angioma that was present in several coronal cerebral sections and was the cause of death. (Right) Like many vascular malformations in the brain, this is a composite vascular malformation in the right corpus striatum, including the head of the caudate nucleus and the internal capsule . An area of telangiectasia is a classic punctate patch. Large venous channels are in the same general vascular distribution.

(Left) A typical incidental venous malformation with a wide distribution is in the right occipital white matter with little cortical involvement . (Right) This angiogram shows a dural arteriovenous fistula draining upward from the left transverse sinus into the basal ganglia . Most intracranial dural arteriovenous fistulas originate in association with a dural venous sinus. The patient presented with basal ganglia hemorrhage and was treated by Onyx and intravascular glue embolization.

(Left) H&E stain of a middle cerebral artery shows a normal, wavy internal elastic lamina that ends at the aneurysmal neck . The aneurysmal wall is irregular and fibrotic . Subarachnoid blood surrounds the sac that is intact in this field. (Right) The fibrous wall of a saccular aneurysm is seen where the rupture site is filled by a delicate fibrin (and cellular) plug or fibrin net. The fibrin net is thought to be disrupted easily by blood flow, and this may be the cause of acute rebleeding prior to interventional therapy.

Microscopic Features (Left) This mycotic aneurysm, seen in cross section with H&E stain at low magnification, arose from a bacterial infection of the arterial wall. The wall is replaced by acute inflammatory cells and tissue debris , predisposing to rupture. (Right) A dilated AVM channel has an irregular wall with focal calcification . The lumen was embolized with Onyx polymer seen as discrete, black particles that promote thrombosis. Foreign-body giant cells can respond to Onyx, as seen here.

(Left) Elastin stain (blueblack) at low magnification shows the reduplicated internal elastic lamina of an AVM artery ending at the transition directly into a dilated, irregular vein. Systolic pressure acts directly on the venous wall. (Right) A cavernous angioma in the medulla, seen at medium magnification, has back-to-back dilated vessels with variable wall thickness, without intervening parenchyma. Focal dystrophic ossification and old blood pigment were present.

(Left) An extensive incidental cerebellar telangiectatic malformation, seen in part at low magnification, is formed of many very thinwalled, dilated, small and large vessels with scant adventitia. The abnormal vascular tree has scattered branches. (Right) This small, incidental capillary hemangioma of back-toback, dilated, thin-walled, capillary-like vessels in cerebral white matter is seen at low magnification. Capillary-like refers to the thin walls, not the wide lumina.

Organ System Approach to Autopsy: Postoperative/Post-Interventional Death

CEREBRAL ANEURYSM AND VASCULAR MALFORMATION

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SECTION 1

Transplantation

Heart Transplant

III-1-2

Lung Transplant

III-1-8

Kidney Transplant

III-1-12

Liver Transplant

III-1-22

Pancreas Transplant

III-1-28

Bone Marrow Transplant

III-1-32

Deceased Donor Autopsy

III-1-36

Disease Process Approach to Autopsy: Transplantation

HEART TRANSPLANT

This autopsy heart from a patient with cardiac transplantation shows severe cardiac allograft vasculopathy with near complete occlusion of the left anterior descending artery .

TERMINOLOGY Synonyms

Antibody-mediated rejection (AMR): Humoral rejection, vascular rejection

Cardiac allograft vasculopathy (CAV): Transplant coronary artery disease, transplant vasculopathy, allograft arteriopathy, transplant arteriosclerosis

This photomicrograph shows a well-demarcated lymphoid aggregate deep in the myocardium . This most likely represents "deep" Quilty effect, a clinically insignificant and enigmatic finding in cardiac allografts.

Antibody binding to capillary antigen presented by endothelium activates endothelial signaling and cell activity Antibody binding initiates complement cascade Complement split products and other chemoattractants lead to macrophage aggregation within injured vessels

Cardiac Allograft Vasculopathy

Arterial narrowing due to concentric intima

ETIOLOGY/PATHOGENESIS Cellular Rejection (CR)

T-cell-mediated host response to allografted heart stimulated by "foreign" human leukocyte (HLA) and other antigens expressed in graft tissue Class I antigens (HLA-A, -B, and -C) are constitutively expressed on most cells in heart, especially vascular endothelium Class II antigens (HLA-DP, -DQ, and -DR) are constitutively expressed on vascular endothelium, resident macrophages Presentation of antigen occurs to T cells directly or indirectly via antigen-presenting cells (APCs) and endothelial cells T-cell antigen stimulation leads to graft injury Activated T cells produce proinflammatory cytokines Activated CD8-positive cytotoxic T cells participate in cytotoxic killing of graft myocytes Activated T cells activate B cells and can stimulate donor-specific antibody production

Antibody-Mediated Rejection

Antibody-mediated host response to allografted

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heart with damage from complement activation and antibody dependent cellular cytotoxicity

thickening by proliferating smooth muscle cells and fibroblasts, leading to chronic ischemia with secondary myocyte changes and interstitial fibrosis Proposed mechanisms include Immunologic Ongoing endothelial injury (such as with persistent or repetitive AMR) Increased T-helper cell activity HLA mismatch Nonimmunologic CMV infection Coagulation cascade and fibrin deposition Traditional atherosclerotic risk factors

CLINICAL ISSUES Epidemiology Incidence

Most rejection episodes occur within 6 months post transplant ~ 30% of recipients have some rejection during 1st year post transplant Cellular and antibody-mediated rejection (AMR) can occur simultaneously CAV incidence post transplant 8% at 1 year 20% at 3 years 30% at 5 years 50% at 10 years

Key Facts Etiology

Cellular rejection

T-Cell mediated host response to allografted heart stimulated by "foreign" human leukocyte (HLA) and other antigens expressed in graft tissue Antibody-mediated rejection Antibody-mediated host response to allografted heart with damage with complement activation Cardiac allograft vasculopathy Arterial narrowing due to concentric intima thickening by proliferating smooth muscle cells and fibroblasts

Clinical Issues

Most rejection episodes occur within 6 months post transplant

Presentation

Asymptomatic presentation is most common Symptoms occur only with moderate or severe ACR

Macroscopic Pathology Rejection

May appear grossly normal

Cardiac allograft vasculopathy

Epicardial and intramyocardial artery involvement

Microscopic Pathology Cellular rejection

Perivascular/interstitial mononuclear inflammation Myocyte damage in association with mononuclear inflammation Antibody-mediated rejection Capillary endothelial cell swelling and injury Positive staining for complement (C4d and C3d) Cardiac allograft vasculopathy Marked concentric intima thickening

MACROSCOPIC FEATURES External Examination

and include symptoms associated with heart failure Risk factors associated with cellular rejection (CR) Noncompliance with immunosuppressive regimen Diarrhea, vomiting interfering with medication absorption Infections Untoward effects/interference of other medications Drastic changes in weight Risk factors associated with AMR Young, female Multiparity Presensitization (panel reactive antibody or single antigen bead) Previous transplantation Multiple transfusions

Median sternotomy Other scars

Treatment

Cardiac Allograft Vasculopathy

Options

Cellular rejection Mild rejection (ISHLT 1R) may resolve spontaneously (~ 85%) Pulse corticosteroids or modification of baseline calcineurin inhibitor dose Anti-thymocyte globulin Antibody-mediated rejection Corticosteroids, augmented immunosuppressives Rituximab, bortezomib Plasmapheresis Cardiac allograft vasculopathy Stents, mTOR inhibitors to stop progression

IMAGE FINDINGS

Disease Process Approach to Autopsy: Transplantation

HEART TRANSPLANT

Coronary bypass grafting (harvest sites) Ventricular assist device, driveline exit site Chest tubes Congestive heart failure Edema Ascites Hepatomegaly Sepsis/DIC Petechiae, ecchymoses

Rejection

Myocardial mottling, global May appear grossly normal Epicardial and intramyocardial artery involvement Vein involvement Subendocardial ischemic changes Interventions (e.g., stenting)

Complications

Infection (pneumonia, urinary tract, abscess, meningitis, pyelonephritis)

Malignancy (masses, metastases, lymphadenopathy, splenomegaly)

Medication toxicity (cushingoid features, nephrosclerosis, adrenal atrophy)

Biopsy Sites

Right ventricle apical trabeculations Predominantly septal, but may be on free wall aspect as well

General Features Echocardiography Angiography

Cardiac allograft vasculopathy

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Disease Process Approach to Autopsy: Transplantation

HEART TRANSPLANT

MICROSCOPIC PATHOLOGY Cellular Rejection

Must be distinguished from CR Prominent capillary vascularity within lymphoid aggregates

Perivascular/interstitial mononuclear inflammation,

B cells admixed in lymphoid aggregate

predominantly composed of activated lymphocytes and macrophages Myocyte damage in association with mononuclear inflammation Damage is not myocyte necrosis but rather encroachment of inflammatory cells into myocyte borders leading to architectural distortion In severe ACR, neutrophils, &/or eosinophils may be present; such rejection is usually mixed with AMR Grading International Society of Heart Lung Transplantation (ISHLT) 2004 grading schema intended for biopsy, but may be applied loosely (1R, 2R, 3R) Alternatively, descriptive diagnosis of severity could be given (mild/moderate/severe; focal/diffuse, etc.)

Biopsy Sites

Antibody-Mediated Rejection

C4d to assess AMR (frozen tissue for

Histopathology

Capillary endothelial cell swelling and injury Interstitial edema, hemorrhage Adherence of macrophages to endothelium Severe cases show edema, hemorrhage, karyorrhexis, vasculitis, and thrombi Occasional neutrophils, eosinophils Immunopathology Positive staining for complement (C4d and C3d) CD68 positive intravascular macrophages

Fibrosis with entrapped myocytes and variable amount of mononuclear inflammation

"Harvesting" or Perioperative Ischemic Damage (for Fresh Transplants)

Mixed infiltrate and coagulation necrosis secondary to perfusion-related damage to myocardium

Resolves in 1st weeks post transplant

ANCILLARY TESTS Immunohistochemistry

CD3, CD20, may be used to rule out post-transplant lymphoproliferative disorder and Quilty effect

immunofluorescence, or else paraffin immunohistochemistry methods) CD68 to identify intravascular macrophages, which would support diagnosis of AMR

SELECTED REFERENCES 1.

Cardiac Allograft Vasculopathy Epicardial coronary arteries

Marked concentric intima thickening Smooth muscle cell proliferation Intimal inflammatory cells Variable lipid, foamy macrophages Intramyocardial arteries Myointimal proliferative changes Endothelialitis Perivascular fibrosis Myocardium Subendocardial sarcoplasmic vacuolization Myocyte hypertrophy, interstitial fibrosis Rare infarct like changes

Other Conditions

Post-transplant lymphoproliferative disorder EBV-positive lymphoproliferation Polyclonal/polymorphous or monoclonal (lymphoma-like) Infections CMV Toxoplasma Chagas Recurrent amyloid

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Quilty Effect

Nodular subendocardial lymphoid aggregates

Well circumscribed, rounded May extend or be seen deep to endocardium as well

2. 3.

5. 6.

Berry GJ et al: The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 32(12):1147-62, 2013 Kittleson MM et al: Antibody-mediated rejection. Curr Opin Organ Transplant. 17(5):551-7, 2012 Kobashigawa J et al: Report from a consensus conference on antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 30(3):252-69, 2011 Lu WH et al: Diverse morphologic manifestations of cardiac allograft vasculopathy: a pathologic study of 64 allograft hearts. J Heart Lung Transplant. 30(9):1044-50, 2011 Tan CD et al: Update on cardiac transplantation pathology. Arch Pathol Lab Med. 131(8):1169-91, 2007 Marboe CC et al: Nodular endocardial infiltrates (Quilty lesions) cause significant variability in diagnosis of ISHLT Grade 2 and 3A rejection in cardiac allograft recipients. J Heart Lung Transplant. 24(7 Suppl):S219-26, 2005 Stewart S et al: Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 24(11):1710-20, 2005 Rowan RA et al: Pathologic changes in the long-term transplanted heart: a morphometric study of myocardial hypertrophy, vascularity, and fibrosis. Hum Pathol. 21(7):767-72, 1990

Microscopic Features (Left) This photomicrograph from a cardiac allograft at autopsy shows a small perivascular lymphocytic infiltrate , without obvious myocyte injury. This would be consistent with mild cellular rejection. (Right) A more diffuse lymphocytic infiltrate is seen in this cardiac allograft at autopsy. There is still no obvious or definite myocyte injury, so it would be considered mild. The ISHLT grading system is intended for biopsies, and caution should be taken when applying this to autopsy.

Disease Process Approach to Autopsy: Transplantation

HEART TRANSPLANT

(Left) This photomicrograph of a heart allograft at autopsy shows a lymphoid inflammatory infiltrate with rare eosinophils , associated with multifocal myocyte injury , consistent with more severe rejection. Clinical correlation would be needed to determine the role of rejection in the cause of death. (Right) This allograft heart at autopsy also showed marked perivascular infiltrate with several foci of myocyte injury , consistent with severe rejection.

(Left) This photomicrograph shows trabecular myocardium from the right ventricle of a transplant heart at autopsy. There are rounded lymphoid aggregates without interstitial extension, consistent with Quilty effect. (Right) At higher magnification, Quilty effect shows proliferating capillaries . This is helpful in the differential diagnosis with cellular rejection.

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Disease Process Approach to Autopsy: Transplantation

HEART TRANSPLANT

Microscopic Features (Left) This high-power photomicrograph of cardiac transplant myocardium at autopsy shows prominent intravascular mononuclear cells , a hallmark of antibody-mediated rejection. Immunostaining for complement (C4d, C3d) &/or macrophages (CD68) should be performed to complete the diagnostic workup. (Right) This trichrome stain shows another feature prominent in antibody-mediated rejection: Interstitial edema . The capillaries also show intravascular mononuclear cells.

(Left) This high-magnification view of transplant myocardium at autopsy shows more severe venular changes with transmural mononuclear inflammation and focal karyorrhectic debris . Complement stains were positive in this case. (Right) In severe rejection, it can be difficult to distinguish cellular rejection features from those of severe antibody-mediated rejection. Several eosinophils are seen in this case of severe rejection. Complement staining is helpful in cases like this.

(Left) Immunofluorescence staining of this cardiac allograft at autopsy is positive for C4d deposition. Capillaries are seen in cross section and longitudinal section . (Right) C4d staining can also be performed using immunohistochemistry techniques in paraffin sections at autopsy. The capillaries are strongly and diffusely positive . The staining is crisp, linear, and circumferential, all features that are helpful in excluding false-positive artifact staining.

III 1 6

Artifacts Confused With Acute Rejection (Left) This epicardial coronary artery from a transplanted heart at autopsy shows significant allograft vasculopathy . There are also small, depressed, old subendocardial infarctions in the territory of this artery. (Right) This angiogram in a cardiac transplant patient shows areas of tapered narrowing , consistent with graft vasculopathy. Since this is only a "luminogram," the degree of cross-sectional stenosis is likely to be greater than anticipated based on the angiogram.

Disease Process Approach to Autopsy: Transplantation

HEART TRANSPLANT

(Left) This low-power photomicrograph of an epicardial coronary artery from an allograft heart at autopsy shows near complete luminal occlusion. The intima has been expanded by smooth muscle cells and collagen . (Right) This elastic stain highlights the internal elastic lamina . The narrowing of this artery is due to an increase in collagen and proliferating vascular smooth muscle cells in the intimal layer (inside the internal elastic lamina).

(Left) This epicardial branch coronary artery from a transplanted heart at autopsy also shows inflammation, largely confined to the intima . There is also an unusual amount of epicardial fibrosis . (Right) Prominent subendocardial myocyte vacuolization change is seen in this allograft with cardiac allograft vasculopathy. This finding suggests ongoing chronic ischemia leading to "hibernating" myocardium.

III 1 7

Disease Process Approach to Autopsy: Transplantation

LUNG TRANSPLANT

This SLT case shows the right native lung with interstitial fibrosis denoted by a cobblestone appearance and a left allograft with postsurgical pleural adhesions and thickening from other complications.

TERMINOLOGY Abbreviations

Orthotopic lung transplant (OLT), single lung transplant (SLT), bilateral lung transplant (BLT), living donor lobar lung transplantation (LDLLT)

ETIOLOGY/PATHOGENESIS Pathogenesis of Complications Following Lung Transplantation

Primary graft dysfunction (PGD): Multifactorial, mild

III 1 8

to severe injury to allograft occurring within 72 hours of transplantation Incidence of severe PGD ~15-35% early morbidity and mortality, length of mechanical ventilation and hospital stay, shortand long-term mortality, risk of bronchiolitis obliterans syndrome (BOS) Clinically progressive hypoxemia with radiographic infiltrates without other identifiable causes Exclusion criteria: Cardiogenic pulmonary edema, pneumonia and aspiration, hyperacute cellular rejection, and pulmonary venous obstruction Pathogenesis not completely understood; inflammatory and immunological repair responses appear to be key controlling mechanisms following ischemia and reperfusion Donor-inherent, donor-acquired, recipient, and operative variables have all been identified Infectious disease Lung transplant compromises normal host defenses (e.g., cough and mucociliary clearance), leaving recipients more susceptible than other solid organ transplant recipients to infections CMV and other DNA viruses; community-acquired respiratory viruses; bacterial, nontuberculous

This right native lung shows interstitial fibrosis , and the left allograft has only mild peribronchial fibrosis . The patient died 2 months post transplant with severe pseudomembranous colitis and sepsis.

mycobacterial, and fungal infections must all be considered Bacterial infections are most common in 1st few weeks post transplant Most infections occur within 3 months to 1 year post transplant, but lifelong risk due to immunosuppression Cytomegalovirus (CMV) donor-recipient matching and viral prophylaxis; has not eliminated risk for CMV pneumonia Aspergillus and Candida species most common fungal infections, involving bronchial anastomotic site &/or lung Anastomotic complications Pulmonary arterial or venous obstruction is rare but has high mortality Intraoperative pressure gradient measurement and transesophageal echocardiography have improved outcomes Early signs include unexplained hypoxia, particularly with pulmonary hypertension Airway complications Airway complications estimated to cause 2-5% of mortalities 6 major types: Anastomotic necrosis and dehiscence, infection, excessive endoluminal granulation tissue formation, bronchomalacia, bronchial stenosis, bronchial fistulae Acute cellular rejection (ACR) and antibody-mediated rejection (AMR) At least 1/3 of lung transplant patients have acute rejection within 1 year post transplantation Acute rejection rarely a direct cause of death but risk for subsequent BOS and may susceptibility to infection when immunosuppression intensified Patients present with fever, cough, dyspnea, and radiographic infiltrates in which major differential diagnosis is infection Chronic lung allograft dysfunction (CLAD) and BOS

Key Facts Clinical Issues

Major long-term mortality mostly attributable to

transplantation exceed those of most other solid organ transplants Major post-transplant complications likely to be encountered at autopsy Primary graft dysfunction Infectious disease Anastomotic complications Airway complications Rejection (acute &/or chronic) Malignancy Most infections occur within 3 months to a 1 year post transplant, but persistent lifelong risk due to immunosuppression

Macroscopic Pathology

Graft failure and mortality rates for lung

Main limitation to better long-term survival; pathogenesis poorly understood Recent International Society for Heart and Lung Transplantation (ISHLT) data: Incidence of BOS 48% at 5 years post transplant and 76% at 10 years Patients present with cough, dyspnea, and irreversible decrease in pulmonary function tests over time malignancy risk due to preexisting risk factors (such as smoking) and immunosuppression Incidence: 13% between 5 and 10 years post transplant Malignancies include skin cancer, post-transplant lymphoproliferative disorder, lung cancer, and other common solid organ tumors Recurrence of nonneoplastic native disease Hyperacute cellular rejection Rare complication that occurs during or shortly after transplantation due to preformed donor-specific antibodies (DSAs) that react immediately with lung allograft Characterized by neutrophilic margination, vasculitis, fibrinoid necrosis, vascular thrombosis, and infarction

CLINICAL ISSUES Epidemiology Incidence

2014 ISHLT Registry data includes > 47,000 adult lung transplant recipients and > 3,700 heart-lung transplant recipients Major indications for lung transplantation Chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), primary arterial hypertension (PAH), cystic fibrosis SLT is used most frequently for COPD and IPF BLT is used in diseases such as cystic fibrosis and sarcoidosis where incidence of coexistent infection is high

infection &/or chronic lung allograft failure

Evaluate anastomotic sites Procure fresh tissue for ancillary studies Examine allograft and native lung (if present) for evidence of consolidation, hemorrhage, and masses

Microscopic Pathology

Variable histologic and sometimes nonspecific findings such as pulmonary edema, hemorrhage, and diffuse alveolar damage, requiring clinical correlation Special stains should be used to exclude infection and to assess chronic airway rejection

Both SLT and BLT have been used in treatment of pulmonary arterial hypertension Age Lung transplantation successful in pediatric and adult patients with nonneoplastic lung disease Older patients (> 65) undergoing lung transplant has , although data indicate that age may negatively impact long-term outcomes and incidence of certain post-transplant complications such as malignancy

Disease Process Approach to Autopsy: Transplantation

LUNG TRANSPLANT

Prognosis

In USA, adult lungs have been allocated according to lung allograft score (LAS) since 2005 LAS has reduced transplant wait list deaths, but data suggests that the practice has resulted in higher post-transplant mortality Graft failure and mortality rates for lung transplantation exceed those of most other solid organ transplants Short-term outcomes have markedly improved with current 3-month survival 90% and 1-year survival ~ 80% 5-year survival rate is ~ 50% and 10-year survival rate is ~ 30% Major long-term mortality attributable to infection &/or chronic lung allograft failure

MACROSCOPIC FEATURES External Examination

Surgical techniques vary for single and bilateral lung transplants Single lung: Lung with worst function replaced or right lung if equal lung dysfunction Incision usually from beneath the shoulder blade across chest to sternum Bilateral lung Incision usually from axilla to sternum to opposite axilla (clamshell)

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Disease Process Approach to Autopsy: Transplantation

LUNG TRANSPLANT Thoracotomy sites/scars should be inspected for signs of dehiscence or infection Chest tubes and endotracheal tubes and vascular access lines assessed for appropriate placement, as they are present Signs of complications of transplantation and chronic lung disease Sepsis: Petechiae, jaundice Chronic hypoxia: Clubbing of fingers (hypertrophic osteoarthropathy)

Internal Examination

Depending on post-transplant interval and history of postoperative complications, lungs may or may not be densely adhesed to chest wall Inspect mediastinum and pleura for evidence of fistulae or infection

Organ Examination

Identify and inspect anastomotic sites (mainstem bronchi, pulmonary artery, and pulmonary veins) Note that pulmonary venous anastomosis is indirect and accomplished by recipient left atrium to donor left atrium sutures Particular attention should be paid to bronchial anastomotic site(s) Site(s) may be grossly characterized as well healed, with granulation tissue, necrosis limited to mucosa or extending through wall, or signs of infection Following procurement of fresh tissue for culture or other ancillary studies such as immunofluorescence, lungs should be inflated with formalin for overnight fixation Examine allograft and native lung (if present) for evidence of consolidation, hemorrhage, or masses Other organs: Features of shock (hepatic necrosis, acute tubular injury, ischemic bowel), complications of therapy (renal scarring and hypertensive heart disease [calcineurin inhibitor therapy]), pseudomembranous colitis (antibiotics)

MICROSCOPIC PATHOLOGY Histologic Features

Acute T-cell-mediated cellular rejection (ACR)

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Based on extent of perivascular and interstitial lymphocytic infiltrates acute lung injury There may also be component of airway inflammation Antibody-mediated rejection (AMR) Diagnosis of exclusion and requires comprehensive serologic, microbiologic, and pathologic correlation Histologic features nonspecific: Acute lung injury and neutrophilic infiltration of alveolar capillaries C4d immunohistochemical staining is used, but it is difficult to interpret and has poor sensitivity Chronic rejection Eccentric submucosal fibrosis or obliterative scarring of small airways (bronchiolitis obliterans)

Distal airway narrowing results in more proximal bronchiectasis Extensive sampling may be necessary in addition to trichrome and elastin stains to better highlight obliterated airways Aspiration is common in lung transplant patients Scattered multinucleated giant cell or granulomas are occasionally seen as incidental finding Infection is always within differential diagnosis and should be rigorously excluded Primary graft dysfunction Diffuse alveolar damage without evidence of infection or other etiology Other organs Kidney: Calcineurin inhibitor toxicity: Nodular hyaline arteriolosclerosis of arterioles (chronic), "foamy" cytoplasm of proximal tubular epithelial cells (acute), thrombotic microangiopathy Shock changes: Ischemic necrosis of organs Infection: Viral inclusions (CMV, HSV, adenovirus) in organs and tissues, suppurative inflammation (bacterial and fungal), and granulomatous inflammation (mycobacteria)

ANCILLARY TESTS Immunofluorescence

Portion of lung may be frozen for C4d staining; paraffin immunohistochemistry for C4d also may be performed

Microbiology

Cultures, histochemistry, immunohistochemistry, in situ hybridization, and molecular studies for infection, as indicated

REPORTING CRITERIA Transplantation Cause of Death

Directly related to or a known complication

Specify type of transplant (single or bilateral) and time elapsed since allograft transplant Findings directly related to transplantation Rejection Infection, particularly in association with immunosuppression Drug toxicity Anastomotic complications Unrelated to transplantation, if appropriate

SELECTED REFERENCES 1. 2.

Todd JL et al: Update in lung transplantation 2013. Am J Respir Crit Care Med. 190(1):19-24, 2014 Wallace WD et al: Update on pathology of antibodymediated rejection in the lung allograft. Curr Opin Organ Transplant. 19(3):303-8, 2014 Yusen RD et al: The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report--2014; focus theme: retransplantation. J Heart Lung Transplant. 33(10):1009-24, 2014

Lung Allograft Pathology at Autopsy (Left) This gross photograph shows an intact suture line at the pulmonary arterial anastomosis. (Right) This gross photograph shows an intact suture line at the left atrial anastomotic site. Tan-white endocardium now covers the blue suture material.

Disease Process Approach to Autopsy: Transplantation

LUNG TRANSPLANT

(Left) The bronchial anastomosis is particularly susceptible to complications. This patient developed a necrotizing infection at the anastomotic site , which led to fatal bleeding into the airway. (Right) Note the reduced caliber of the airway in comparison to its companion vessel in this example of chronic allograft rejection. This is due to scar tissue forming in the submucosa of the small airway .

(Left) This trichrome stain of chronic allograft rejection helps to highlight the submucosal fibrosis in the small airway. The epithelium is intact but protruding into the lumen of the airway due to the submucosal fibrosis. (Right) In this image of chronic allograft rejection, this airway lumen has been completely obliterated by fibrosis. The residual mural smooth muscle remains .

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Disease Process Approach to Autopsy: Transplantation

KIDNEY TRANSPLANT

Artery shows endothelial swelling and lifting with intima infiltration by mononuclear cells (endothelialitis) involving > 25% of the lumen, consistent with acute rejection Banff type IIA.

Arteriole shows fibrinoid necrosis of the wall in this case of acute rejection. Fibrinoid necrosis or transmural inflammation are features of rejection Banff type III.

TERMINOLOGY Synonyms

Kidney allograft

Definitions

Allograft implantation for treatment of end-stage renal disease (ESRD) Allograft types Living, related Living, unrelated Deceased

ETIOLOGY/PATHOGENESIS Diseases Leading To Kidney Transplant

Glomerular diseases: 12-16% of patients with chronic

renal failure (CRF)

Hypertensive nephrosclerosis: 29-38% of patients with CRF

Diabetic nephropathy: ~ 50% of patients with CRF and 1/3 of patients in dialysis

Polycystic kidney disease: ~ 3% of patients with CRF

CLINICAL ISSUES Epidemiology Incidence

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Antibody-mediated rejection (AMR) Hyperacute rejection in < 0.5% of transplants Acute antibody-mediated rejection ~ 25% of acute rejection episodes Acute T-cell-mediated rejection episode occurs in 5-10% of kidney transplants in 1st year post transplant Chronic cellular rejection major cause of long-term allograft failure Drug toxicity

Calcineurin inhibitor: Thrombotic microangiopathy 2-5%, chronic toxicity 60-70% at 2 years Infections BK nephropathy present in ~ 5% of kidney transplanted patients on tacrolimus and mycophenolate mofetil Recurrence of primary disease Membranous glomerulopathy: 30% IgA nephropathy: 13-50% Membranoproliferative glomerulonephritis type 1: 20-50% Dense deposit disease: > 80% Lupus nephritis: Up to 30% Focal segmental glomerulosclerosis: 20-40% Diabetic nephropathy : > 50% Most common de novo glomerular disease Membranous nephropathy: 0.5-9% of allografts Focal segmental glomerulosclerosis: 10-20% of allografts Anti-glomerular basement membrane disease: 3-5% of Alport patients allografts Post-transplant lymphoproliferative disease 1 allograft may be present

Organ Examination Hyperacute rejection

Parenchyma is purple-blue with soft, flaccid consistency Hemorrhagic infarction and swelling Large and medium-sized artery thrombi Acute AMR Enlarged and swollen graft Focal hemorrhage and infarcts Acute cellular rejection Enlarged and swollen graft Pale or with mottled hemorrhagic appearance in more severe forms Kidney rupture may occur Chronic rejection Small shrunken kidney

MICROSCOPIC PATHOLOGY Histologic Features Hyperacute rejection

Early features Endothelial swelling & necrosis Neutrophilic margination within peritubular and glomerular capillaries Microthrombosis in capillaries, arterioles, and small arteries Tubular necrosis Late features Interstitial hemorrhage Neutrophilic inflammation Intravascular thrombosis Cortical and medullary necrosis

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Disease Process Approach to Autopsy: Transplantation

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KIDNEY TRANSPLANT Acute AMR

Early features Neutrophilic margination in glomerular and peritubular capillaries Tubular necrosis Late features Endothelial injury Microvascular thrombosis Mesangiolysis Larger arteries with transmural arteritis Interstitial edema and mononuclear inflammation Acute cellular rejection Interstitial mononuclear inflammation and edema Inflammation may include variable numbers of plasma cells and eosinophils Tubulitis involving nonatrophic tubules Acute tubular injury Endothelialitis (mononuclear cells underneath endothelium) present in more severe type of cellular rejection, most common in larger arteries Transmural inflammation and arteriolar or arterial fibrinoid necrosis in most severe cases Chronic cellular rejection Global &/or segmental glomerulosclerosis Interstitial mononuclear inflammatory infiltrate in scarred and nonscarred areas Interstitial fibrosis with nonspecific pattern Tubular atrophy and tubulitis in atrophic and nonatrophic tubules Arteries with intimal fibrosis, foamy cells, and mononuclear inflammation in intima Chronic AMR Transplant glomerulopathy Duplication of capillary basement membrane Negative immunofluorescence Electron-dense deposits are not identified Transplant arteriopathy Fibrous intimal thickening with infiltrating lymphocytes &/or monocytes Peritubular capillaritis characterized by presence of mononuclear cells within peritubular capillaries Drug toxicity Calcineurin inhibitor, acute toxicity Functional toxicity without morphologic changes Isometric vacuolization in tubular epithelial cells Thrombotic microangiopathy Calcineurin inhibitor, chronic toxicity Secondary segmental glomerulosclerosis Interstitial fibrosis and tubular atrophy with striped pattern Arterioles and most distal portions of interlobular arteries affected by nodular hyaline deposits in smooth muscle cells with beaded circular pattern Infections BK nephropathy Pleomorphic interstitial inflammation: Lymphocytes, plasma cells, eosinophils, and neutrophils Viral cytopathic changes: Nuclear enlargement, nuclear inclusions with ground-glass appearance Glomerular diseases recurrent or de novo show morphology similar to primary disease

Immunofluorescence and electron microscopy examination are necessary for diagnosis Knowledge of primary disease leading to end-stage renal disease is indispensable for classification of glomerular lesions

ANCILLARY TESTS Immunohistochemistry

SV40 immunohistochemical stain necessary to confirm BK polyomavirus nephropathy

CMV stain C4d by immunohistochemistry can be used when no frozen tissue is available

Immunofluorescence Hyperacute rejection

C3, C4d in capillaries, arterioles and small arteries; fibrin staining in microvasculature Acute and chronic AMR C4d(+) in peritubular capillaries Glomerular diseases Panel of IgG, IgA, IgM, C3, C1q, light chains, and albumin should be performed when there is history of proteinuria and cause of end-stage renal disease was glomerulonephritis

Electron Microscopy Transmission

Electron dense deposits can be identified and confirm diagnosis of glomerular diseases recurrent or de novo Multilamellation of peritubular capillaries is characteristic of chronic AMR Transplant glomerulopathy is characterized by expansion of lamina rara interna by electron-lucent material

REPORTING CONSIDERATIONS Banff Classification Background

Classification is currently based on light microscopy, immunofluorescence, or immunohistochemistry and, in some cases, electron microscopy Diagnostic categories defined by semiquantitative scores Opportunity to add other modalities, e.g., gene expression Refinement occurs through biannual open meetings to reach consensus on additions/changes based on published, confirmed evidence Widely used in drug trials Sample adequacy is 7 glomeruli and 2 arteries and should be noted

Banff Categories

Category 1: Normal Category 2: Antibody-mediated rejection (C4d[+]) Requires acute or chronic tissue injury or inflammation, evidence of antibody interaction

with tissue (usually C4d in peritubular capillaries [PTC]), and circulating antibodies reactive to donor endothelium Acute antibody-mediated rejection I: Acute tubular injury II: Peritubular &/or glomerular capillary inflammation (neutrophils), thrombi III: Arterial involvement by transmural arteritis, &/or arterial fibrinoid necrosis and medial smooth muscle necrosis with inflammatory infiltrate in vessel Chronic antibody-mediated rejection Chronic tissue injury includes GBM duplication without immune complex deposition (transplant glomerulopathy), PTC basement membrane multilamination (usually seen by electron microscopy), transplant arteriopathy, and interstitial fibrosis and tubular atrophy Often manifested by mononuclear cells in PTC (capillaritis) &/or glomeruli (transplant glomerulitis) Hyperacute rejection Usually due to preformed antibody, e.g., antibodies to HLA or ABO antigens C4d deposition without evidence of active rejection Category 3: Borderline or suspicious for acute cellular rejection Category 4: T-cell-mediated rejection Requires > i1 and t2 or > v0; C4d negative for pure T-cell-mediated rejection Acute T-cell-mediated rejection IA: Interstitial inflammation (> 25% of unscarred cortex) and foci of moderate tubulitis (> 4 mononuclear cells per tubular cross section) IB: Interstitial inflammation (> 25% of unscarred cortex) and foci of severe tubulitis (> 10 mononuclear cells per tubular cross section) IIA: Mild to moderate intimal arteritis (< 25% of luminal area) (v1) IIB: Severe intimal arteritis (> 25% of luminal area) (v2) III: Transmural arteritis &/or fibrinoid necrosis of medial smooth muscle (v3) Chronic active T-cell-mediated rejection Chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, formation of neointima) Category 5: Interstitial fibrosis and tubular atrophy, no evidence of any specific etiology Use only when etiology of IF/TA is unknown Formerly known as chronic allograft nephropathy (CAN) Category 6: Other Changes considered not due to rejection Calcineurin inhibitor toxicity, polyomavirus infection, and others

Caveats

Biopsies may meet criteria for 2 diagnoses Detailed criteria established only for rejection categories

Reproducibility of certain categories and features is limited

Banff Scoring Categories

Interstitial inflammation (i)

Mononuclear inflammation in nonfibrotic areas; excludes subcapsular cortex and perivascular infiltrates i0: < 10% of nonfibrotic cortex i1: 10-25% i2: 26-50% i3: > 50% Do not include fibrotic areas in denominator Tubulitis (t) Mononuclear cells in tubules; for longitudinal sections count per 10 tubular epithelial nuclei t0: No mononuclear cells in tubules t1: Foci with 1-4 cells/tubular cross section t2: Foci with 5-10 cells/tubular cross section t3: Foci with > 10 cells/tubular cross section Need at least 2 foci of tubulitis to be present Vascular inflammation (v) Mononuclear cells in intima or media of arteries or medial necrosis v0: No arteritis v1: Intimal arteritis in < 25% of lumen (minimum = 1 cell, 1 artery) v2: Intimal arteritis in 25% of lumen in 1 artery v3: Transmural arteritis &/or medial smooth muscle necrosis (fibrinoid necrosis) Glomerulitis (g) % of glomeruli with increased mononuclear cells in capillaries g0: No glomerulitis g1: < 25% of glomeruli g2: 25-75% of glomeruli g3: > 75% of glomeruli Interstitial fibrosis (ci) % of cortex with fibrosis ci0: 5% ci1: 6-25% ci2: 26-50% ci3: > 50% Tubular atrophy (ct) % of cortex with atrophic tubules ct0: 0% ct1: 25% ct2: 26-50% ct3: > 50% Arterial fibrointimal thickening (cv) % of narrowing of lumen of most severely affected artery cv0: 0% cv1: 25% cv2: 26-50% cv3: > 50% Note if lesions characteristic of chronic cellular rejection are present (inflammatory cells in intima, foam cells, breaks in internal elastica or lack of fibroelastosis in intima) Transplant glomerulopathy (cg)

Disease Process Approach to Autopsy: Transplantation

KIDNEY TRANSPLANT

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Disease Process Approach to Autopsy: Transplantation

KIDNEY TRANSPLANT % of glomerular capillary loops with duplication of GBM in most affected glomerulus cg0: < 10% cg1: 10-25% cg2: 26-50% cg3: > 50% Mesangial matrix increase (mm) % of glomeruli with mesangial increase, defined as > 2 mesangial cells in width in at least 2 glomerular lobules mm0: 0% mm1: 25% mm2: 26-50% mm3: > 50% Arteriolar hyalinosis (ah) Circumferential or noncircumferential (focal) hyaline ah0: No arterioles with hyaline ah1: 1 arteriole with noncircumferential hyaline ah2: 1 arteriole with noncircumferential hyaline ah3: 1 arteriole with circumferential hyaline Note if peripheral nodules are present Peritubular capillary inflammation (ptc) % of cortical PTC with neutrophils or mononuclear cells ptc0: < 10% PTC with cells ptc1: > 10% with < 5 cells/PTC ptc2: > 10% with 5-10 cells/PTC ptc3: > 10% with > 10 cells/PTC Note whether only mononuclear cells, < 50% neutrophils, or > 50% neutrophils C4d score in PTC (C4d) % of PTC with C4d deposition scored in at least 5 HPF C4d0: 0% C4d1: 1-9% C4d2: 10-50% C4d3: > 50% Note technique used (frozen vs. paraffin) Total inflammation (ti) Includes all cortical inflammation, even subcapsular, perivascular, nodular, and fibrotic areas ti0: < 10% of cortex ti1: 10-25% ti2: 26-50% ti3: > 50%

REPORTING CRITERIA Required Final Report Elements

Cause of death and how it may relate to transplantation

Presence of complications, rejection, recurrent disease, de novo disease, malignancy

SELECTED REFERENCES

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de Kort H et al: The role of electron microscopy in renal allograft biopsy evaluation. Curr Opin Organ Transplant. Epub ahead of print, 2015

8. 9.

10.

11.

12.

13.

14.

Kozakowski N et al: The diffuse extent of peritubular capillaritis in renal allograft rejection is an independent risk factor for graft loss. Kidney Int. Epub ahead of print, 2015 Haas M et al: Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibodyassociated arterial lesions. Am J Transplant. 14(2):272-83, 2014 Haas M: Chronic allograft nephropathy or interstitial fibrosis and tubular atrophy: what is in a name? Curr Opin Nephrol Hypertens. 23(3):245-50, 2014 Naesens M et al: The histology of kidney transplant failure: a long-term follow-up study. Transplantation. 98(4):427-35, 2014 Mengel M et al: Banff 2011 Meeting report: new concepts in antibody-mediated rejection. Am J Transplant. 12(3):563-70, 2012 Sellar s J et al: Understanding the causes of kidney transplant failure: the dominant role of antibodymediated rejection and nonadherence. Am J Transplant. 12(2):388-99, 2012 Racusen LC et al: The pathology of chronic allograft dysfunction. Kidney Int Suppl. (119):S27-32, 2010 Boldorini R et al: Kidney and urinary tract polyomavirus infection and distribution: molecular biology investigation of 10 consecutive autopsies. Arch Pathol Lab Med. 129(1):69-73, 2005 Michalak G et al: Infectious complications after simultaneous pancreas-kidney transplantation. Transplant Proc. 37(8):3560-3, 2005 Sanrom n Budio B et al: Autopsy-determined causes of death in solid organ transplant recipients. Transplant Proc. 36(3):787-9, 2004 Gill JS et al: Mortality after kidney transplant failure: the impact of non-immunologic factors. Kidney Int. 62(5):1875-83, 2002 Porazko T et al: Causes of death among cadaver kidney graft recipients between 1983 and 2000. Transplant Proc. 34(6):2066-7, 2002 Racusen LC et al: The Banff 97 working classification of renal allograft pathology. Kidney Int. 55(2):713-23, 1999

Microscopic Features (Left) Early histologic features of hyperacute rejection shown in this section include margination of neutrophils in peritubular capillaries and tubular epithelial cell necrosis . (Right) In hyperacute rejection, the glomerular capillaries can be involved by microthrombosis . In this case, there is also a thrombus at the glomerular vascular pole . In the adjacent interstitium, edema and mild inflammation are seen . The tubules show epithelial injury .

Disease Process Approach to Autopsy: Transplantation

KIDNEY TRANSPLANT

(Left) In hyperacute rejection, microthrombosis in capillaries and arterioles can be seen in early phase, leading to glomerular ischemic changes. Acute tubular necrosis is also shown in this case. (Right) H&E-stained section shows a large artery nearly completely occluded by a fibrin thrombus in a case of hyperacute rejection. This process occurs immediately or within the 1st hours post transplant. The kidney is usually lost.

(Left) Acute tubular injury can occur as a manifestation of antibodymediated rejection, and it is characterized by sloughing off of epithelial cell lining . Positive C4d and donor-specific antibody are necessary for diagnosis. (Right) Transplant glomerulitis is a morphologic finding indicative of acute antibody-mediated rejection. There is accumulation of mononuclear cells in glomerular capillary lumina . Endothelial swelling can also be present.

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Disease Process Approach to Autopsy: Transplantation

KIDNEY TRANSPLANT

Microscopic Features (Left) Peritubular capillaritis is characterized by mononuclear cells within peritubular capillaries . This finding is a reliable marker of antibodymediated rejection. In this case, there are > 10 mononuclear cells, which would correspond to Banff ptc3. (Right) On silver stain, the basement membranes of the peritubular capillaries are highlighted, facilitating their identification. This is an example of marked peritubular capillaritis .

(Left) C4d immunofluorescence staining highlights the peritubular capillaries that appear as circles when transversely sectioned with bright linear staining. This finding supports antibody-mediated rejection. Immunofluorescence is a more sensitive method for diagnosis. (Right) C4d immunohistochemical stain can be performed if frozen tissue is not available. Although less sensitive, this method is useful for diagnosis of AMR. Linear staining in the PTCs is seen.

(Left) Acute T-cell-mediated rejection occurs commonly during the 1st year post transplant. Mononuclear interstitial inflammation with tubulitis , tubular injury, and interstitial edema are characteristic. Banff scoring for tubulitis in this case is t2. (Right) In some cases of T-cell-mediated rejection, the predominant cell in the inflammatory infiltrate is the plasma cell . In this case, significant interstitial edema is also seen .

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Gross and Microscopic Features (Left) In some cases of acute T-cell-mediated rejection, the inflammatory infiltrate may contain numerous eosinophils admixed with mononuclear cells. It may not be possible, in this setting, to differentiate Tcell-mediated rejection from acute interstitial nephritis. (Right) Endothelialitis is a finding indicative of a more severe T-cell-mediated rejection. It is characterized by inflammatory cells underneath the endothelium . This is an example of Banff IIA.

Disease Process Approach to Autopsy: Transplantation

KIDNEY TRANSPLANT

(Left) In more severe cases of cellular rejection, endothelialitis with lifting of endothelial cells with subintimal lymphocytes can be identified. This case corresponds to Banff IIB with involvement of > 25% of the lumen. (Right) This case of Tcell-mediated rejection Banff IIB shows on silver stain a large artery with lifting of the endothelium and presence of inflammatory cells and some foamy macrophages involving nearly completely the artery circumference.

(Left) This specimen is from a transplant patient who died from a cardiovascular event 8 years post transplant. Immunosuppression had been withdrawn due to allograft failure. The external surface is covered by a white connective tissue, and there are areas of hemorrhage. (Right) On cut surface, the allograft shows thinned cortex and . medullary congestion The pyelocaliceal system is not dilated, but increase in adipose tissue is seen at the hilum .

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Disease Process Approach to Autopsy: Transplantation

KIDNEY TRANSPLANT

Microscopic Features (Left) Section from failed allograft 8 years post transplant shows several globally sclerosed glomeruli , which is a nonspecific finding. There is interstitial fibrosis and tubular loss. Inflammatory infiltrate is also present. (Right) In allografts with chronic injury, interstitial fibrosis and tubular atrophy are common findings. They usually do not show any specific pattern, and chronic inflammatory infiltrate accompanies these changes.

(Left) In chronic active allograft vasculopathy, there is concentric intimal proliferation in the arteries with associated subintimal lymphocytes . (Right) In an advanced case of chronic cellular rejection, the arteries show marked intima proliferation with no significant inflammatory cells. It may be difficult to differentiate from changes due to hypertension; however, no significant elastic duplication is seen, which is most characteristic of hypertensive arteriosclerosis.

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(Left) Transplant glomerulopathy is characterized by "double contours" in the capillary . The Banff scoring walls is performed in the most affected glomerulus. This case corresponds to Banff cg3. There is also segmental sclerosis . (Right) Electron microscopy examination confirms diagnosis of transplant glomerulopathy. In early stage, there is expansion of the subendothelial space by electron lucent material . These features should be differentiated from other causes of TMA.

Microscopic Features (Left) Drug toxicity is a complication that can cause allograft failure. Acute features of calcineurin inhibitors toxicity can manifest as thrombotic microangiopathy. In this case, there are numerous fibrin thrombi in glomerular capillaries . (Right) Tubular isometric vacuolization is nonspecific and can be seen in intravenous immunoglobulin therapy, contrast media, and osmotic agent-induced nephropathy and is also a manifestation of acute CNI toxicity, seen here.

Disease Process Approach to Autopsy: Transplantation

KIDNEY TRANSPLANT

(Left) Striped tubular atrophy and fibrosis , a pattern of alternating atrophic and nonatrophic parenchyma, might arise secondary to narrowing of small arterioles/ arteries along the medullary ray. The findings are seen in several ischemic conditions, including hypertension, calcineurin inhibitor toxicity, etc. (Right) Nodular hyalinosis of an interlobular artery can be seen in chronic calcineurin inhibitor toxicity.

(Left) BK polyomavirus nephropathy is a complication seen in solid organ transplants. It occurs in 5-10% of kidney allografts. It usually manifests 12-18 months post transplant. The characteristic findings are the basophilic, glassyappearing nuclear inclusions , and a mixed interstitial inflammatory infiltrate. (Right) Polyomavirus can be demonstrated in tissue section by immunohistochemistry. The infected cells show nuclear staining .

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Disease Process Approach to Autopsy: Transplantation

LIVER TRANSPLANT

This dissection shows an intact hepatic artery anastomosis status post liver transplant. (Courtesy P. Lento, MD.)

TERMINOLOGY

Pathogenesis of Complications

Definitions

1 graft dysfunction/nonfunction: 2-20%, hours to days post transplant, multifactorial, preservation/ reperfusion injury Hyperacute/acute humoral rejection: Rare, hours to weeks, preformed (hyperacute) or de novo antidonor antibodies Acute (cellular) rejection: 20-40%, days to months, T-cell-mediated immune injury Fibrosing cholestatic hepatitis: Rare, 1-3 months, type of recurrent hepatitis B or C, rapidly progressive graft failure Early or late complications Infection: 60-80%, bacterial > viral > fungal (Aspergillus and Candida most common) Biliary: 10-25%, early leak/strictures, late strictures 2 to hepatic artery thrombosis/chronic rejection superimposed infection Hepatic artery thrombosis: 2-10%, most common vascular complication Early graft ischemic injury, late ischemic bile duct injury necrosis, superinfection, and stricture Portal vein thrombosis: Rare, early graft dysfunction, late portal hypertension Hepatic vein/IVC obstruction: Rare, kinking, stricture, or thrombosis may venous outflow obstruction and Budd-Chiari syndrome Disease recurrence: Hepatitis C: > 90%; hepatitis B: < 10%; AIH: 20-30%; PBC: 10-30%; PSC: 20-25%; HCC: 30-50% Late complications Chronic rejection: 2-3%, months to years, immunemediated irreversible injury to arteries, veins, bile ducts Nodular regenerative hyperplasia: Up to 80%, may be incidental or portal hypertension

Deceased donor liver transplantation: Replacement of native liver with an allograft liver from a nonliving/ cadaveric donor Living donor liver transplantation: Replacement of native liver with a portion of liver from a living donor (usually a relative)

ETIOLOGY/PATHOGENESIS Reasons for Liver Transplantation Chronic liver failure (most common)

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This dissection shows an intact bile duct anastomosis status post liver transplant. (Courtesy P. Lento, MD.)

Chronic viral hepatitis C (most common), hepatitis B D, alcoholic liver disease, nonalcoholic steatohepatitis (NASH), autoimmune hepatitis (AIH) Biliary diseases: Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), extrahepatic biliary atresia (most common reason in children) Acute liver failure Drug/toxin induced (acetaminophen most common), acute viral hepatitis A, B D or E, AIH, Budd-Chiari syndrome Metabolic diseases Diseases that cause liver injury Wilson disease, -1-antitrypsin deficiency, hemochromatosis Diseases that do not cause liver injury Ornithine carbamoyltransferase deficiency, protein C deficiency, familial amyloidosis Neoplasms Hepatocellular carcinoma (HCC) (usually in setting of cirrhosis) Rare: Cholangiocarcinoma, hepatocellular adenomatosis, epithelioid hemangioendothelioma, hepatoblastoma, metastatic neuroendocrine tumor (NET)

Early complications

Key Facts Etiology

Early complications: Primary graft dysfunction/ nonfunction, hyperacute/acute rejection, fibrosing cholestatic hepatitis Early or late complications: Infection, biliary complications, vascular thrombosis, disease recurrence Late complications: Chronic rejection, de novo disease, nodular regenerative hyperplasia

Clinical Issues

Important elements of chart review: Reason for/ type of transplantation, findings in explanted liver, postoperative course, episodes of rejection, comorbid conditions Causes of death: Infection (most common), technical failure/intraoperative complications, liver/graft De novo disease: Viral hepatitis, AIH, NASH, neoplasia (immunosuppression-related: Posttransplant lymphoproliferative disorder [PTLD], Kaposi sarcoma, skin cancer)

failure, cardiovascular/respiratory failure, multiorgan failure, malignancy 15% mortality rate within 1st year

Macroscopic Pathology Sections to submit

Gross lesions/masses Central and peripheral parenchyma Hepatic artery, portal vein, vena cava, and bile duct anastomoses Deep hilum to include vessels, bile ducts, nerves

Diagnostic Checklist

Cause of death and how it relates to transplantation Presence of post-transplantation complications, recurrent disease, de novo disease, malignancy

Risk factors for complications

Causes of death: Infection/sepsis (most common), technical complications, liver/graft failure, cardiovascular/respiratory failure, multiorgan failure, malignancy

CLINICAL ISSUES

IMAGE FINDINGS

Epidemiology

Radiographic Findings

~ 6,200 liver transplants performed in USA in 2012 Current 5-year survival ~ 70% Rate of retransplantation: Up to 20%, commonly due to primary nonfunction, rejection, hepatic artery thrombosis, or disease recurrence

Presentation

Fever, abdominal pain, jaundice, fatigue, ascites (nonspecific presentation related to many transplantrelated complications) Important elements of chart review Reason for and type of transplantation, preexisting donor lesions (degree of steatosis), findings in explanted liver Operative note with anastomosis details, postoperative course, episodes of rejection, results of postoperative/protocol liver biopsies Immunosuppressive/other drugs, comorbid conditions

Laboratory Tests

transaminases, alkaline phosphatase, bilirubin, viral RNA/DNA levels, -fetoprotein

prothrombin and partial thromboplastin times, international normalized ratio (INR) Leukocytosis, thrombocytopenia, total serum complement (humoral rejection) (+) blood, wound, tissue cultures, (+) new viral titers immunosuppressive drug levels (rejection)

Prognosis

15% mortality rate within 1st year

Disease Process Approach to Autopsy: Transplantation

LIVER TRANSPLANT

CT scan/MR: Cirrhosis, masses, evidence of portal hypertension (ascites, collateral vessel formation, splenomegaly) Angiography: Diagnostic (thrombosis, pseudoaneurysm, stenosis) and therapeutic Cholangiography: Diagnostic (stenosis/stricture, leaks) and therapeutic (stents)

MACROSCOPIC FEATURES Sections to Be Submitted

Liver: Gross lesions/masses, central/peripheral parenchyma, hepatic artery, portal vein, vena cava, and bile duct anastomoses, deep hilum to include vessels, bile ducts, nerves Other organs: Representative sections and sections of any gross pathology

External Examination

Scleral icterus, jaundice, abdominal varices Surgical interventions (wound, drains) Ascites (fluid wave), cachexia (malignancy), cutaneous lesions (squamous cell carcinoma), palpable lymph nodes (PTLD), bruises (allograft liver failure) Hirsutism, central obesity and striae (iatrogenic Cushing syndrome [steroid therapy])

Internal Examination

Ascites, pleural/pericardial effusions, metastatic disease

Organ Examination Liver

Probe and open each of the 4 anastomoses

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Disease Process Approach to Autopsy: Transplantation

LIVER TRANSPLANT Hepatic artery: Usually donor hepatic artery to celiac trunk, open celiac trunk from posterior past splenic artery past gastroduodenal artery to anastomosis Vascular grafts may be present, depending on anatomical variations Biliary (2 types): Common bile duct to common bile duct anastomosis or Roux-en-Y hepatojejunostomy (examine before removing intestines) Note presence of sludge, stones, necrosis, stenosis Portal vein (may be beneath celiac trunk) and upper/lower inferior vena cava Note thrombosis, kinking, strictures Cirrhosis, nodules, necrosis, masses, hemorrhage Other organs Gastric/esophageal varices, esophagitis/ gastroenteritis/colitis ulcers, splenomegaly Lung consolidation/abscesses, targetoid lung lesions with central hemorrhage/necrosis (fungal infection), cystitis, meningoencephalitis Renal cortical pallor and medullary congestion, myocardial mottling, ischemic bowel (shock)

MICROSCOPIC PATHOLOGY Histologic Features Hepatic findings

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Preservation/reperfusion injury: Centrilobular/ perivenular hepatocyte ballooning, necrosis, apoptosis, cholestasis Hyperacute/humoral rejection: Sinusoidal and intravascular fibrin deposition, congestion, hemorrhagic necrosis, (+) immunostain for C4d in portal stroma/vessels and sinusoids Acute (cellular) rejection: Triad of mixed portal inflammation (including large activated lymphocytes), bile duct injury with inflammatory cell infiltration, venular endotheliitis Hepatic artery thrombosis: Geographic infarction/ coagulative necrosis, neutrophils, portal tracts usually spared, subsequent ischemic large bile duct injury necrosis/ulcers/superinfection Vena cava/hepatic vein thrombosis/occlusion (venous outflow obstruction/Budd-Chiari syndrome): Severe perivenular/midzonal congestion, sinusoidal dilatation necrosis Portal vein thrombosis: May be normal or parenchymal atrophy, nodularity, mild portal fibrosis Bile duct obstruction: Portal tract edema, periportal ductular reaction with neutrophils, cholestasis, feathery degeneration of hepatocytes, bile infarcts, bile lakes, secondary biliary cirrhosis Ischemic cholangiopathy: Features of duct obstruction, ulcers/necrosis of large ducts superinfection, secondary sclerosing cholangitis Chronic rejection: Bile duct injury, ductopenia, occlusive foam cell arteriopathy intimal

hyperplasia, fibrous obliteration of veins, perivenular cholestasis Fibrosing cholestatic hepatitis: Periportal/ perisinusoidal fibrosis, hepatocyte ballooning, cholestasis, inflammation Nodular regenerative hyperplasia: Hyperplastic regenerative nodules alternating with compressed atrophic hepatocytes (reticulin stain), no fibrosis Recurrent disease: Hepatitis or cirrhosis related to primary disease Neoplasia: Recurrent from 1 neoplasia or de novo (PTLD, other malignancies) Opportunistic infection: Cytomegalovirus (CMV), herpes simplex virus (HSV), adenovirus, fungal Other organs Shock: Myocardial infarction, acute tubular necrosis Infection: Pneumonia, abscesses central necrosis/ hemorrhage, diffuse alveolar damage, inflammation/ infection of gastrointestinal tract, brain/meninges Exogenous steroid effect: Adrenal gland atrophy

ANCILLARY TESTS Immunohistochemistry

(+) hepatitis B surface and core antigens, CMV, HSV, adenovirus

(+) C4d in humoral rejection

In Situ Hybridization EBER (PTLD, infection)

Special Stains

Routine liver stains (reticulin, trichrome, iron) Elastic: Arterial intimal thickening and portal vein fibrous occlusion in chronic rejection

Gram, fungal, acid-fast bacillus stains

DIAGNOSTIC CHECKLIST Final Report Should Include

Cause of death and how it relates to transplantation Presence of post-transplantation complications, recurrent disease, de novo disease, malignancy

Risk factors for complications

SELECTED REFERENCES 1.

3. 4.

Ayva E et al: Pathological findings of liver allografts evaluated at autopsy. Exp Clin Transplant. 12 Suppl 1:120-5, 2014 Hubscher SG et al: Transplantation pathology. In Burt A et al: MacSween’s Pathology of the Liver. Edinburgh New York: Churchill Livingstone/Elsevier. 853-933, 2012 Alqahtani SA et al: Adult liver transplantation in the USA. Curr Opin Gastroenterol. 27(3):240-7, 2011 Nichols L: Autopsy evaluation of transplant recipients. In Collins KA et al: Autopsy Performance & Reporting. Northfield, IL: College of American Pathologists, 205-17, 2003 Markin RS et al: Main autopsy findings in liver transplant patients. Mod Pathol. 2(4):339-48, 1989

Gross and Microscopic Findings After Liver Transplantation (Left) This dissection shows an intact portal vein anastomosis as it exits the hilum of the donor liver. (Courtesy P. Lento, MD.) (Right) This dissection shows an intact inferior vena cava distal to anastomosis the point of entry into the right atrium . (Courtesy D. Rubin, MD.)

Disease Process Approach to Autopsy: Transplantation

LIVER TRANSPLANT

(Left) This portal tract shows changes of acute cellular rejection, including inflammation composed of lymphocytes and eosinophils , and an injured bile duct with nuclear pleomorphism and lymphocytes infiltrating the epithelium. (Right) In addition to lymphocytes and eosinophils that are characteristic of acute cellular rejection, this portal tract also shows mild endotheliitis with subendothelial inflammation and endothelial cell tufting into the lumen.

(Left) These changes of severe parenchymal congestion and associated hepatocellular necrosis are the sequelae of venous outflow obstruction caused by thrombosis of a hepatic vein. The immediate periportal region is preserved . (Right) This reticulin stain highlights a nodule of hyperplastic hepatocytes surrounded by cords of compressed atrophic hepatocytes that are characteristic of nodular regenerative hyperplasia.

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Disease Process Approach to Autopsy: Transplantation

LIVER TRANSPLANT

Gross and Microscopic Findings After Liver Transplantation (Left) This portal tract shows hepatic arteriole and portal venule branches without an accompanying bile duct, indicative of ductopenia. Ductopenia is a histologic feature of chronic rejection. (Courtesy M. Fiel, MD.) (Right) This portal tract shows the triad of large bile duct obstruction that may be seen in stenosis, strictures, and ischemic injury: Portal tract edema with "blurring" of the interface, bile ductular reaction , and associated neutrophils.

(Left) Fibrosing cholestatic hepatitis is characterized by periportal and sinusoidal fibrosis , ballooning of hepatocytes , and cholestasis . (Courtesy M. Fiel, MD.) (Right) This section from a colon ulcer bed shows nuclear and cytoplasmic inclusions characteristic of cytomegalovirus in an immunosuppressed patient status post transplant.

(Left) Post-transplant lymphoproliferative disorder (PTLD) developed in a patient status post transplant for familial amyloidosis. This section of the transplanted liver shows a large necrotic mass . (Courtesy P. Lento, MD.) (Right) The mass is composed of large atypical plasma cells and lymphocytes with necrosis consistent with PTLD, polymorphic type, with monoclonal plasma cells. (Courtesy P. Lento, MD.)

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Gross and Microscopic Findings After Liver Transplantation (Left) Adenovirus infection in the liver often occurs in the setting of immunosuppression and is characterized by basophilic smudgy intranuclear inclusions and patchy hepatocellular necrosis . (Right) Immunostain for adenovirus is positive in the nuclei of infected hepatocytes.

Disease Process Approach to Autopsy: Transplantation

LIVER TRANSPLANT

(Left) Massive ascites developed in a patient with cirrhosis due to recurrent hepatitis C infection. (Right) This section of lung shows a well-circumscribed "targetoid" mass lesion with central necrosis and hemorrhage typical of fungal infection in an immunosuppressed patient status post transplant.

(Left) Sections through a targetoid mass lesion in the lung of an immunosuppressed patient status post transplant reveal large areas of necrosis and inflammation filling the alveolar spaces . (Right) GMS stain performed on areas of necrosis show numerous septate hyphae with acute angle branching and a bulbous appearance , consistent with Aspergillus species. Cultures grew Aspergillus fumigatus.

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Disease Process Approach to Autopsy: Transplantation

PANCREAS TRANSPLANT

Pancreas allograft section shows septal mononuclear inflammation without acinar or vessel involvement. The cells do not show blastic appearance. This case would be classified as indeterminate for acute rejection.

TERMINOLOGY

CLINICAL ISSUES

Synonyms

Presentation

Definitions

Acute T-cell or antibody-mediated rejection

Pancreas allograft Pancreas allograft implantation from deceased donor for treatment of diabetes mellitus type 1 or type 2 Types of pancreas transplants Simultaneous pancreas/kidney (SPK) Pancreas after kidney (PAK) Pancreas transplant alone (PTA)

ETIOLOGY/PATHOGENESIS Reasons for Pancreas Transplantation

Diabetes mellitus type 1 with kidney failure Diabetes mellitus type 2, insulin-dependent with kidney failure

Pathogenesis of Complications Technical

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Pancreas allograft section shows mixed septal inflammatory infiltrate and ductitis consistent with mild acute T-cell-mediated rejection (Banff grade I).

Allograft thrombosis most common complication and cause of graft loss (~ 16.4% with enteric drainage); risk factors include old donor age, long cold ischemia time, poor surgical technique Infection 1-5%; bacterial, viral, fungal Anastomotic leak: 0.5-2% Pancreatitis Peritonitis chemical or bacterial Bleeding Early immunological Hyperacute rejection rare event with current HLA testing Acute T-cell-mediated rejection (ACR) Acute antibody-mediated rejection (AMR) Late immunological Chronic rejection/graft sclerosis

Thrombosis of allograft will manifest as acute abdomen and graft dysfunction

Usually asymptomatic Serum amylase/lipase levels increase Hyperglycemia Chronic rejection Gradual deterioration in graft function Reduction of urine amylase levels Hyperglycemia needing insulin treatment Risk factors: Episodes of early acute cellular rejection, type of allograft PTA and PAK, HLA mismatch, CMV infection, younger recipient

Treatment Drugs

Immunosuppression with calcineurin inhibitors, mycophenolate mofetil, mTOR inhibitors

Prognosis

SPK survival at 1 year: 86%; immunological loss rate: 1.8%; half life: 13 years

PAK survival at 1 year: 80%; immunological loss rate: 3.7%; half life: 8 years

PTA survival at 1 year: 78%; immunological loss rate: 6.0%; half life: 8 years

IMAGE FINDINGS Ultrasonographic Findings

Doppler ultrasound useful for identification of vascular complications

CT Findings

Peripancreatic collections, hematomas, lymphoceles, abscesses can be identified

Key Facts Terminology

Pancreas allograft implantation from deceased donor for treatment of diabetes mellitus type 1 or type 2

Clinical Issues

Thrombosis of allograft will manifest as acute abdomen and graft dysfunction

Acute T-cell or antibody-mediated rejection may be asymptomatic or show elevation of amylase/lipase or hyperglycemia Chronic rejection manifest with progressive deterioration of graft function

Macroscopic Pathology

Autopsy should be performed as soon as possible to minimize effects from autolysis in graft

Sections to be submitted

Small shrunken mass in case of chronic rejection

MACROSCOPIC FEATURES General Features

Autopsy should be performed as soon as possible to minimize effects from autolysis in graft

External Examination

In abdomen, scar from surgery should be identified

Internal Examination

Graft location and any peripancreatic collection noted Attention to vascular anastomotic sites to identify injury in vessels and thrombosis

Examination for leaks in other anastomotic sites

Organ Examination Gross examination

Graft should be carefully examined and prosected intact with duodenum and enteric or bladder anastomoses Sections to be submitted Cross section of large vessels Several sections from parenchyma to include medium and small vessels Include any area that appears different from surrounding parenchyma Save a frozen piece if C4d is to be performed by immunofluorescence Other studies Cultures should be taken if abscess is identified

MICROSCOPIC PATHOLOGY Histologic Features Allograft thrombosis

Parenchymal necrosis Interstitial hemorrhage Pancreatitis

Cross section of large vessels Several sections from parenchyma to include medium and small vessels

Include any area that appears different from normal parenchyma

Save a sample frozen if C4d is performed by immunofluorescence

Microscopic Pathology

Allograft thrombosis Pancreatitis Hyperacute rejection Acute T-cell-mediated rejection Acute antibody-mediated rejection Chronic rejection Other histologic findings

Neutrophils are the most prevalent inflammatory cell in the infiltrate affecting exocrine pancreas in acute pancreatitis In chronic pancreatitis perilobular and ductal fibrosis with mononuclear inflammation and atrophy of exocrine glands Hyperacute rejection (rare) Fibrinoid necrosis of arteries/veins Vascular thrombosis Parenchymal necrosis Deposit of IgG/C3 in vessel walls Acute T-cell-mediated rejection Mild/grade I Septal mononuclear inflammatory infiltrate with features of activation (blastic lymphocytes, eosinophils) Venulitis Ductitis Perineural inflammation Focal acinar inflammation Moderate/grade II Multifocal acinar inflammation ( 3 foci/lobule) with single cell acinar cell injury and dropout Minimal intimal arteritis: Scattered mononuclear cells in intima or muscularis without endothelial reaction Severe/grade III Severe multifocal/confluent acinar inflammation with focal or diffuse multicellular acinar cell injury/necrosis Moderate intimal arteritis: Mononuclear cells in intima with endothelial injury, fibrin leakage, coating neutrophils &/or macrophages Arteritis: Complete or partial circumferential necrosis due to transmural inflammatory infiltrates Acute antibody-mediated rejection Interacinar capillaritis with neutrophil margination Chronic rejection Perilobular & ductal fibrosis Acinar atrophy

Disease Process Approach to Autopsy: Transplantation

PANCREAS TRANSPLANT

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Disease Process Approach to Autopsy: Transplantation

PANCREAS TRANSPLANT

Banff Schema for Grading Pancreas Allograft Rejection Category

Pathologic Findings

Normal

Absent inflammation or inactive inflammation not involving vessels, ducts, or acini; no fibrosis or acinar atrophy or injury

Indeterminate

Active septal inflammation not fulfilling criteria of mild cellular rejection

Cell-mediated rejection

Mild/grade I: Active septal inflammation with venulitis, ductitis or perineural inflammation, focal acinar inflammation (2 foci maximum and minimal or absent acinar injury; moderate/grade II: Multifocal (not confluent) acinar inflammation, acinar injury and drop-out &/or minimal arteritis; severe/grade III: Diffuse acinar inflammation with focal or diffuse acinar cell necrosis &/or moderate arteritis &/or transmural arteritis; chronic active: Chronic allograft arteriopathy

Antibody-mediated rejection

C4d positive, confirmed donor specific antibodies and graft dysfunction; hyperacute rejection: Immediate graft necrosis ( 1 h); accelerated AMR: Graft necrosis occurring hours or days post transplant; acute AMR: No histologic findings, neutrophilic or mononuclear capillaritis, thrombosis, vasculitis, parenchyma necrosis

Chronic allograft rejection/graft sclerosis

Mild/grade I: Fibrosis in < 30% with irregular acinar contours, normal central areas; moderate/grade II: Fibrosis > 30-60% involving peripheral acini and central areas; severe/grade III: Fibrosis > 60% with isolated areas of acinar tissue &/or islets

Other histologic diagnosis

Pancreatitis, viral infection, ischemic injury, recurrent autoimmune disease, post-transplant lymphoproliferative disorder

Ductal ectasia Mononuclear inflammatory infiltrate Atrophy or disruption of islets Arteriopathy with concentric narrowing Other histologic findings Post-transplant ischemic pancreatitis: Neutrophilic inflammation, foamy macrophages in septa or involving acini in severe cases, fat necrosis, hemorrhage, edema Bacterial/fungal infections: Variable, acute, chronic, purulent, necrotizing, granulomatous Cytomegalovirus pancreatitis: Septal, acinar patchy chronic inflammation with cytopathic changes in acinar, endothelial or stromal cells Recurrent autoimmune disease: Mononuclear inflammation involving islets, no inflammation in later stages after loss beta cells

ANCILLARY TESTS Immunohistochemistry

C4d should be performed when AMR is suspected

Immunofluorescence

C4d should be performed when AMR is suspected

Special Stains

Trichrome for evaluation of fibrosis Gram, AFB, and GMS in cases of infections

REPORTING CRITERIA Final Report Should Include

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Cause of death and how it relates to transplantation Presence of post-transplant complications, de novo diseases, rejection, malignancy

SELECTED REFERENCES 1.

Watson CJ: The current challenges for pancreas transplantation for diabetes mellitus. Pharmacol Res. Epub ahead of print, 2015 2. de Kort H et al: Diagnosis of early pancreas graft failure via antibody-mediated rejection: single-center experience with 256 pancreas transplantations. Am J Transplant. 14(4):936-42, 2014 3. Haas M et al: Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibodyassociated arterial lesions. Am J Transplant. 14(2):272-83, 2014 4. Weems P et al: Pancreas transplantation in type II diabetes mellitus. World J Transplant. 4(4):216-21, 2014 5. Niederhaus SV et al: Acute cellular and antibody-mediated rejection of the pancreas allograft: incidence, risk factors and outcomes. Am J Transplant. 13(11):2945-55, 2013 6. Yates A et al: Imaging pancreas transplants. Br J Radiol. 86(1030):20130428, 2013 7. Drachenberg CB et al: Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema. Am J Transplant. 11(9):1792-802, 2011 8. Drachenberg CB et al: Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel. Am J Transplant. 8(6):1237-49, 2008 9. Takahashi H et al: Analysis of acute and chronic rejection in multiple organ allografts from retransplantation and autopsy cases of multivisceral transplantation. Transplantation. 85(11):1610-6, 2008 10. Humar A et al: Chronic rejection: the next major challenge for pancreas transplant recipients. Transplantation. 76(6):918-23, 2003 11. Drachenberg CB et al: Pancreas transplantation: the histologic morphology of graft loss and clinical correlations. Transplantation. 71(12):1784-91, 2001

Microscopic Features (Left) Acute cell-mediated rejection is characterized by mixed inflammatory infiltrate initially involving septa and venules that in more severe cases extends to the acini , as is shown in this case of moderate (Banff grade II) rejection. There is associated acinar epithelial injury. (Right) Antibodymediated rejection can occur in pancreas allografts, and positive peri acinar capillaries for C4d by immunofluorescence or immunohistochemical stain is required for diagnosis as well as positive DSA.

Disease Process Approach to Autopsy: Transplantation

PANCREAS TRANSPLANT

(Left) Trichrome stain of a pancreas allograft highlights areas of fibrosis . There is exocrine parenchyma still uninvolved by fibrous tissue. In this case, the extent of fibrosis was approximately 50%, which is consistent with moderate chronic allograft rejection (Banff grade II). (Right) Pancreas allograft section shows marked fibrosis (graft sclerosis) consistent with severe chronic rejection (Banff grade III) with only scattered islets still preserved.

(Left) Pancreas allograft section of a large artery shows allograft vasculopathy characterized by concentric intima fibrous thickening . These features are similar to other graft arteriopathy occurring in other solid organ transplants. (Right) Pancreatitis is a complication that may affect the pancreas allograft and has to be differentiated from cellular rejection. The inflammatory cells in pancreatitis are mainly neutrophils that may be placed in septi and involving acini .

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Disease Process Approach to Autopsy: Transplantation

BONE MARROW TRANSPLANT

Pus-filled cavitary lesions are seen in the right upper lobe lung of a patient with recent bone marrow transplantation. Fungal hyphae consistent with Aspergillus were seen microscopically.

TERMINOLOGY Abbreviations

Bone marrow transplantation (BMT)

Synonyms

Hematopoietic stem cell transplantation (HSCT)

Definitions

Intensive medical therapeutic procedure, undertaken in phases Harvesting: Hematopoietic stem cells collected from peripheral blood using apheresis Autologous: Harvested from self Allogeneic: Harvested from another person (HLA matched) Conditioning: Diseased bone marrow is eradicated by chemotherapy &/or radiation (myeloablation) Transplantation: Hematopoietic stem cells infused, engraft in bone marrow to repopulate immune system

ETIOLOGY/PATHOGENESIS Bone Marrow Transplantation Indications Leukemia Myelodysplasia Lymphoma Aplastic anemia Sickle cell disease, thalassemia Immune deficiency syndromes Inherited metabolic disorders

CLINICAL ISSUES

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Assessing Engraftment

Review antemortem complete blood count

Previous bone marrow biopsies (if available)

Autopsy photomicrograph of the vertebral marrow in a patient with recent bone marrow transplant shows decreased cellularity and serous atrophy of the marrow fat , indicating incomplete engraftment.

Molecular chimerism studies

Recurrent Hematolymphoid Disease (Relapse) Leukemia

Blast %, comparison to primary

Lymphoma

Staging (nodal, extranodal, bone marrow) EBV infection (post-transplant lymphoproliferative disorders)

Graft-vs.-Host Disease (GVHD) Skin: Rash, eczematous plaques

Face, trunk, palms, and soles most common

GI tract

Watery diarrhea

Liver

Cholesteatotic hepatitis

Infectious Complications Immunocompromised host

Incomplete granulocyte &/or lymphocyte engraftment Change in adaptive immunity repertoire Immunosuppressive drugs (to prevent rejection and GVHD) in allogeneic transplants Opportunistic infections Fungal Angioinvasive Aspergillus Cryptococcus Mucor Mycobacterial Mycobacterium avium complex Miliary tuberculosis Viral CMV, HSV, VZV Parasitic Toxoplasma Nosocomial infections Methicillin-resistant Staphylococcus aureus

Key Facts

Skin samples (taken along "Y" incision lines), intestinal samples, liver sections

Terminology

Sources of hematopoietic stem cells

Autologous: Harvested from self Allogeneic: Harvested from another person (HLA matched)

Clinical Issues Engraftment

Review antemortem complete blood count Previous bone marrow biopsies (if available) Molecular chimerism studies

Macroscopic Pathology

Microscopic Pathology Engraftment

Assess marrow for cellularity and trilineage hematopoiesis Relapsed disease Leukemia, lymphoma, plasma cell dyscrasia Infectious complications Fungal, viral, parasitic, and bacterial Special stains (Gram, MS, AFB)

Infectious complications

Postmortem culture of any pus or drainage Opportunistic infections Graft-versus-host disease (GVHD)

Grading of Graft-vs.-Host Disease Skin

GI tract (Often not possible to accurately grade due to autolysis)

Grade I: Focal or diffuse vacuolar change at dermal-epidermal junction

Grade I: Single cell apoptosis of crypt epithelium (No accepted grading scheme)

Grade II: Epidermal spongiosis with apoptotic keratinocytes

Grade II: Destruction of single crypts or glands with apoptotic crypt abscesses

Disease Process Approach to Autopsy: Transplantation

BONE MARROW TRANSPLANT

Liver

Bile duct epithelial cell damage with minimal inflammation or duct loss

Grade III: Subepidermal clefting, more Grade III: Focal mucosal necrosis with ulceration Epithelial cell vacuolization and attenuation spongiosis, and more dyskeratotic keratinocytes Grade IV: Complete epidermal detachment with Grade IV: Diffuse mucosal necrosis with extensive epidermal necrosis denudation

Vancomycin-resistant Enterococcus

MACROSCOPIC FEATURES External Examination

Venous infusion catheters and ports Signs of infection

Skin lesions

Petechiae, ecchymoses (coagulopathy, sepsis, DIC) Abscesses, cellulitis Bulky adenopathy

Skin samples (taken along "Y" incision lines), intestinal samples, liver sections Infectious complications Gross purulence, abscesses in organs, body cavities, psoas muscle Postmortem culture of any pus or drainage

MICROSCOPIC PATHOLOGY Histologic Features Engraftment/relapse

Assess marrow for cellularity and trilineage hematopoiesis Lymph nodes Overall cellularity, follicles and germinal centers Spleen histology Red pulp (cords and sinuses) White pulp cellularity, germinal centers Extramedullary hematopoiesis Liver, kidneys, lungs, lymph nodes

Internal Examination

Bone marrow sampling (for engraftment/relapse evaluation) Expressed from individual ribs after chest plate removed Compress bone 1-2 cm from cut surface and scrape extruded marrow into fixative Cancellous bone from vertebral bodies or sternum Sliced thin with vibrating saw and decalcified before processing Flow cytometry usually limited value due to low viability postmortem Hematolymphoid organs Splenomegaly, splenic infarction Lymph nodes Hilar, retroperitoneal, mesenteric, pelvic GVHD

Ductopenia

SELECTED REFERENCES 1.

Seftel MD et al: High rate of discordance between clinical and autopsy diagnoses in blood and marrow transplantation. Bone Marrow Transplant. 40(11):1049-53, 2007 Al-Saidi F et al: Relationship between premortem and postmortem diagnosis in critically ill bone marrow transplantation patients. Crit Care Med. 30(3):570-3, 2002

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Disease Process Approach to Autopsy: Transplantation

BONE MARROW TRANSPLANT

Microscopic Features (Left) A hilar lymph node sampled at autopsy 1 week after bone marrow engraftment shows retained lymph node architecture with a capsule and intact trabecular sinuses . However, there is a paucity of lymphocytes and no follicles are seen. There is also considerable autolysis. (Right) This oil immersion field of the bone marrow shows a potential complication of bone marrow transplantation, hemophagocytic syndrome. The macrophage cytoplasm is filled with erythrocytes .

(Left) Features of graft-versushost disease are seen in this skin sample. There is interface dermatitis with satellite cell necrosis characterized by apoptotic keratinocytes with adjacent lymphocytes . (From DP: Nonneoplastic Dermatopathology.) (Right) This autopsy lung section from a patient with bone marrow transplant several months ago shows features of recurrent diffuse large B-cell lymphoma . This is recognizable despite significant autolysis in the lung.

III 1 34

(Left) Recurrent large cell lymphoma is seen in the kidney of this bone marrow transplant patient. Despite the autolysis of tubules and glomeruli , atypical hyperchromatic lymphocytes are apparent in the lymphomatous infiltrate. (Right) Myriad Cryptococcus neoformans organisms are seen in this glomerulus of a patient with immunosuppression for graftversus-host disease following bone marrow transplantation. Note the virtual absence of inflammation.

Microscopic Features (Left) After removing the calvarium of this bone marrow patient, clouding of the meninges and purulence in the sulci were apparent. Meningitis was confirmed histologically. (Right) Wedge section of the kidney from a bone marrow transplant patient autopsy shows a nodular focus of recurrent lymphoma (confirmed histologically).

Disease Process Approach to Autopsy: Transplantation

BONE MARROW TRANSPLANT

(Left) Fungal hyphae with 45 angle branching consistent with Aspergillus species can be seen by H&E in this autopsy lung sample from a bone marrow transplant patient. (Right) Silver staining highlights the morphology of the fungal elements. Cross sections of the hyphae can be seen, along with characteristic 45 angle branching of Aspergillus species.

(Left) Acid-fast stain shows innumerable positivestaining thread-like bacilli within macrophages in a lymph node. Several mycobacterial species can give this appearance in immunocompromised patients, with the avium intracellulare group being most common. (From DP: Gastrointestinal.) (Right) Autopsy heart section shows myocarditis with encapsulated yeast forms morphologically consistent with Cryptococcus.

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Disease Process Approach to Autopsy: Transplantation

DECEASED DONOR AUTOPSY

This large area of excised skin from an organ and tissue donor should not be mistaken for trauma. There is also an incision from long bone and tendon retrieval .

TERMINOLOGY

MACROSCOPIC FEATURES

Definitions

External Examination

There are special considerations when performing an autopsy on organ &/or tissue donors Deceased donor Individual whose next of kin (or through premortem indications) consents to organ &/or tissue donation Organ donors are most often declared brain dead (donation after brain death [DBD]): Kidneys, heart, lungs, liver, pancreas, intestine Patients may also donate some organs after circulatory (cardiac) death (DCD): Kidneys (most frequent), infrequently liver and lung Tissue donors may be DCD: Heart valves, skin, bone, tendon Eyes and corneas are often donated Corneas transplanted, eyes often used for research Donation consent does not mean autopsy consent Next of kin of deceased donors who die a natural death must complete separate autopsy consent Donors who die an unnatural death are sent to local medical examiner for investigation Organ procurement organization (OPO) Local organizations certified by center for Medicare and Medicaid service (CMS) to evaluate potential donors and arrange for recovery and transport of transplanted organs

CLINICAL ISSUES Laboratory Tests

Local OPO will screen donors extensively for

III 1 36

These feet are awkwardly oriented due to the removal of the long bones of the leg. The lower portion of the long incision that ran the length of the leg is visible . This should not be mistaken for trauma.

potentially transmissible disease and for markers of organ function prior to donation OPO can provide that data to pathologist responsible for autopsy

Remarkable for effects of organ and tissue donation

Abdominal and chest incisions from organ donation procedure Linear incisions along extremities in bone donation Awkward orientation of boneless extremity (do not mistake for trauma) Large areas of extraction of skin and dermis by dermatome Rectangular areas of loss of skin with exposed soft tissue and fat Do not mistake for trauma Eye caps used following eye donation Plastic cups shaped like eyeballs that are placed in eye socket and have corrugated outer edge to hold eyelid in place Difficult to open eyelid when eye cap is in place Data regarding appearance of eye and conjunctiva can be retrieved from local eye bank

Internal Examination Note all donated organs

Organ Examination

Remaining organs examined as per complete autopsy Try to determine underlying cause of death

Most commonly related to CVA, subarachnoid hemorrhage, intracerebral hemorrhage, brain tumor without metastasis, hypoxia Drug overdose, head trauma cases would be examined by medical examiner Identify features related to brain death: Will vary with duration of brain death and pre-donation physiologic alterations Mottling of subendocardial (myocardial ischemia related to vasoconstriction)

Key Facts Terminology

Macroscopic Pathology

Kidneys, heart, lungs, liver, pancreas, intestine Some organs rarely used after circulatory (cardiac) death (DCD): Kidneys (most frequent), infrequently liver and lung

intracerebral hemorrhage, brain tumor without metastasis, hypoxia Identify features related to brain death: Pulmonary edema, visceral ischemia, disseminated intravascular coagulation

Organs usually procured in brain dead donors:

Increased weight and increased fluid in lungs (pulmonary edema) Intestinal ischemia (visceral hypoperfusion) Petechiae, hemorrhages (disseminated intravascular coagulation) Adrenal gland stress response: ACTH secreted during stress response causes lipid depletion in adrenal gland Grossly adrenal cortex loses yellow color

MICROSCOPIC PATHOLOGY Histologic Features

Subendocardial myocardial coagulative necrosis myocyte necrosis with contraction bands Intraalveolar pink fluid (pulmonary edema) Coagulative necrosis of bowel mucosa (intestinal ischemia) Centrilobular hepatic necrosis (visceral ischemia) Coagulative necrosis or degenerative changes of tubular epithelial cells of kidney (intestinal hypoperfusion) Lipid depletion in cells of zona fasciculata of adrenal cortex (stress response)

Brain death usually: CVA, subarachnoid hemorrhage,

DIFFERENTIAL DIAGNOSIS Brain Death: Primary vs. Secondary Effects

May be difficult to distinguish hypoperfusion changes due to brain death from pre-brain death physiologic instability Correlation with clinical history may help distinguish timing of organ alterations

Disease Process Approach to Autopsy: Transplantation

DECEASED DONOR AUTOPSY

REPORTING CRITERIA OPO Notification

Findings of potential clinical impact to any organ or tissue recipients must be reported to OPO as soon as recognized Included but not limited to malignancy and infection All reports are shared with OPO Highlight any information of potential impact to donor family (potentially heritable diseases, community acquired communicable disease, etc.)

SELECTED REFERENCES 1.

Lipshutz GS et al: Death from donor-transmitted malignancy despite emergency liver retransplantation. Liver Transpl. 9(10):1102-7, 2003 Keating MR et al: Transmission of invasive aspergillosis from a subclinically infected donor to three different organ transplant recipients. Chest. 109(4):1119-24, 1996

IMAGE GALLERY

III (Left) The cause of death in this tissue donor was an acute myocardial infarction . It is important to note any possible communicable/ transmissible diseases during donor autopsies. (Center) This unsutured sternal incision was the consequence of thoracic organ donation. present from resuscitation. The muscle appears brown as a consequence of embalming prior to There is also soft tissue hematoma autopsy. (Right) The cause of death for this donor was intracerebral hemorrhage that extends into subarachnoid space .

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SECTION 2

Infection-Related Death

Systemic Infection/Sepsis Overview HIV/AIDS

III-2-38

Shock and Sepsis

III-2-42

Organ System Infection Bronchopneumonia

III-2-48

Infective Endocarditis

III-2-52

! Enterocolitis

III-2-56

Viral Hepatitis

III-2-60

Urosepsis

III-2-64

Disease Process Approach to Autopsy: Infection-Related Death

HIV/AIDS

This coronal section of brain was taken from a patient with CNS Toxoplasma gondii. Note the areas of cystic necrosis in the cortex and basal ganglia.

TERMINOLOGY General Features of AIDS Pathology Loss of cell-mediated immunity

Opportunistic infection Most common cause of death Often reactivation of latent infection Virus-associated neoplasms likelihood of disseminated disease Autopsy often reveals unexpected findings Minimal gross findings (e.g., poorly formed or absent granulomas for fungi and mycobacteria) Minimal inflammatory response despite numerous organisms Cultures, special stains, and sampling of grossly normal tissue are essential Complications of highly active antiretroviral therapy (HAART) Immune reconstitution inflammatory syndrome (IRIS): Sudden worsening of symptoms with onset of therapy and rebound of CD4 count Coronary artery disease

This H&E histologic section of brain was taken from a patient with Toxoplasma gondii. A cyst containing numerous bradyzoites is seen.

Mycobacteria: (Mycobacterium avium complex [MAC], less frequently Mycobacterium tuberculosis MTB); other species more unusual Often miliary rather than cavitary/granulomatous Stains and cultures are crucial Other bacteria Bacterial pneumonia common in AIDS autopsies Particularly encapsulated organisms (e.g., Pneumococcus, Haemophilus influenzae) Viruses Cytomegalovirus (CMV) Often coinfection (e.g., with Pneumocystis) Patterns: 1-3 cm necrotic nodules, ARDS pattern Gross changes can be subtle Herpes simplex virus (HSV) and varicella zoster virus (VZV) Variable inflammatory response; may be necrotizing Tumors Kaposi sarcoma (KS) Lungs: Hemorrhagic lesions Airways: Raised red to purple plaques

Cardiovascular Manifestations

MACROSCOPIC FEATURES Pulmonary Manifestations Fungi

III 2 38

Diffuse or patchy areas of dark red, airless lung Pneumocystis jirovecii: Most common opportunistic infection in AIDS patients Cryptococcus neoformans: Diffuse or miliary patterns Histoplasma capsulatum: Endemic areas (Mississippi and Ohio River valleys) Classic histoplasma granuloma: Cut section shows concentric lamellae Disseminated cases lack granulomas Coccidioides immitis: Mostly in endemic, arid areas (Southwestern USA)

Coronary artery disease

In part from metabolic effects of antiretroviral medications Dilated cardiomyopathy: Mechanism unknown Infections: Toxoplasma gondii, fungi, CMV, mycobacteria Often part of disseminated infections Tumors: KS and lymphoma

Gastrointestinal Manifestations Fungi

Candida albicans White plaques, discrete or confluent, on inflamed mucosa Typically oral and esophageal Histoplasma: Hepatosplenomegaly

Key Facts Terminology

HIV/AIDS is 6th leading cause of death worldwide and is 2nd leading cause of death in low income countries (WHO 2012 data) Autopsies on AIDS patients require meticulous attention to personal protection Respiratory precautions Double gloving Splash protection Opportunistic infections are most common cause of death Impaired immune response may dramatically alter gross and microscopic findings Gross findings may be minimal; histologic sampling of grossly normal tissue is essential

Mycobacteria

MAC Typically in small bowel with minimal gross change (mild villous blunting) Can involve liver; less often stomach and colon Other bacteria: Salmonella, Shigella, Campylobacter Significantly higher risk for enteric bacterial infections Viruses CMV Variable mucosal changes: From minimal changes to ulceration with hemorrhage Typically in colon (especially distal) and esophagus (especially distal) Esophagus: Linear and oval ulcers HSV Typically esophageal First vesicles, then punched out shallow ulcers surrounded by normal mucosa Parasites Cryptosporidium: In 10-20% of diarrheal stool samples from AIDS patients Minimal gross changes: Mild villous blunting Rarely associated with acalculous or gangrenous cholecystitis Tumors KS: Submucosal red macules or violaceous nodules

Lymph Nodes and Bone Marrow

Persistent generalized lymphadenopathy seen early in disease course

Fungi

Cryptococcus, Histoplasma, and Coccidioides: Lymphadenopathy and marrow involvement Mycobacteria MAC: May involve lymph nodes and marrow; gross changes often subtle Tumor KS: May involve lymph nodes Lymphoma: Usually B-cell non-Hodgkin, often high grade Primary effusion lymphoma: Associated with HHV-8

Histologic changes may be minimal and granulomas may be poorly formed or absent Histochemical stains, immunoperoxidase, and culture can dramatically increase diagnostic yield Besides opportunistic infections, patients with AIDS are at increased risk for disseminated bacterial infections Viral-associated tumors can be seen in AIDS patients Kaposi sarcoma Lymphoma, particularly CNS lymphoma and primary effusion lymphoma Condylomas and squamous cell carcinoma of oral cavity and anorectum Antiretroviral therapy is highly effective but carries certain risks (IRIS, increased risk of coronary artery disease)

Central Nervous System Parasites

Toxoplasma gondii: Most common CNS opportunistic pathogen Necrotic, abscess-like lesions, often multiple, predominantly in gray matter Fungi Cryptococcus: Meningoencephalitis; destructive lesions, sometimes gelatinous Mycobacteria MTB: Miliary lesions; MAC rarely produces gross lesions Viruses CMV: May produce no gross lesions HSV: Lesions may be diffuse (typically frontotemporal in immunocompetent patients) Tumors Lymphoma: 90% EBV-associated diffuse large Bcell lymphoma; also Burkitt lymphomas, T-cell lymphomas Vacuolar myelopathy Progressive multifocal leukoencephalopathy

Disease Process Approach to Autopsy: Infection-Related Death

HIV/AIDS

Skin

Viruses

HSV and VZV: Vesicular skin lesions; VZV lesions may be diffuse rather than dermatomal HPV: From condylomas to squamous cell carcinoma of oral cavity and anorectum KS Pink to violet patches, plaques, angiomatoid nodules Distribution in AIDS patients: Arms, oral mucosa, trunk, face, soles

MICROSCOPIC PATHOLOGY Histologic Features Pulmonary

Pneumocystis jerovicii

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Disease Process Approach to Autopsy: Infection-Related Death

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HIV/AIDS H&E: Foamy, pink, refractile intraalveolar fluid; sparse inflammation GMS stain: Spherical, crescentic, and cup-shaped organisms, 5-7 m Cryptococcus neoformans H&E: Variable inflammation; granulomas PAS or GMS stain: 4-6 m yeast with doubly refractile walls and narrow-based budding Mucicarmine to highlight capsule Histoplasma capsulatum: Granulomas may be poorly formed or absent H&E: Variable inflammation; often subtle foamy histiocytic infiltrate PAS or GMS stain: 2-5 m oval to round budding yeast; may be inside histiocytes Coccidioides immitis H&E: Affected areas can show a rim of eosinophilia PAS and GMS stain: Large (30-60 m) spherules full of 2-5 m spherules; hyphae with barrelshaped arthroconidia Mycobacteria: Granulomas may be poorly formed or absent MTB: Often miliary with necrosis MAC: Often just subtle infiltrate of foamy macrophages; special stains crucial AFB stain: Typically intracellular, red bacilli; usually 3-5 m long by 0.2-0.6 m wide Other bacteria May have typical histology of bacterial pneumonia with intraalveolar acute inflammation Severely immunosuppressed patients may have cavitary lesions CMV Variable patterns (necrotic nodules, interstitial pneumonitis, diffuse alveolar damage) H&E: CMV-infected cells: Enlarged (25-50 m) cells, single "owl’s-eye" 20 m nuclear inclusion, multiple 1-3 m cytoplasmic inclusions Immunoperoxidase stains helpful KS Distribution: Pleural, bronchovascular bundles, interlobular septa H&E: Typically spindled cells with slit-like space containing extravasated red cells Immunoperoxidase: Positive for CD34, factor VIII antigen, HHV8 Gastrointestinal Candida albicans H&E: Acutely inflamed, eroded mucosa GMS and PAS: Yeast (2-7 m) and pseudohyphae MAC H&E: Infiltrate of foamy macrophages AFB stain: Typically intracellular, red bacilli; usually 3-5 m long by 0.2-0.6 m wide CMV: Immunoperoxidase very helpful CMV cytopathic changes in stromal, endothelial and glandular cells at ulcer base HSV: Immunoperoxidase very helpful

Esophagus: Infected squamous cells at ulcer periphery H&E: Typical cytopathic changes: Multinucleated giant cells, ground glass nuclei, nuclear molding, nuclear inclusions Consider VZV if immunostains negative for HSV Cryptosporidium H&E: Faint 2-4 m oval to round oocysts on epithelial cell surfaces Kinyoun, Giemsa, and PAS positive Lymph nodes and bone marrow Persistent generalized lymphadenopathy: Reactive changes with florid follicular hyperplasia Fungi and mycobacteria H&E: Necrotizing granulomas, poorly formed granulomas, or histiocytic infiltrate without granulomas Special stains are essential Central nervous system T. gondii H&E: Necrotizing encephalitis, arteritis, thrombosis; organisms at periphery of necrotic zone Wright or Giemsa: Tachyzoites; 3-4 m ovals or crescents, dark blue cytoplasm and eccentric nucleus Cysts: Up to 40 m with numerous bradyzoites

SELECTED REFERENCES 1.

2. 3. 4.

5. 6.

Guimar es LC et al: Morphological changes in the digestive system of 93 human immunodeficiency virus positive patients: an autopsy study. Rev Inst Med Trop Sao Paulo. 54(2):89-93, 2012 Fuster V et al: Hurst’s the Heart. 13th ed. New York: McGraw Hill New York, 2011 Singer EJ et al: Neurologic presentations of AIDS. Neurol Clin. 28(1):253-75, 2010 Fenoglio-Preiser CM et al. Gastrointestinal Pathology, an Atlas and Text. 3rd ed. Philadelphia: Lippincott, Williams and Wilkins, 2008 Wormser GP: AIDS and Other Manifestations of HIV Infection. 4th ed. Amsterdam: Elsevier, 2004 Masliah E et al: Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS. 14(1):69-74, 2000

Gross and Microscopic Features (Left) H&E histologic section of lung infected with Pneumocystis jerovicii shows the mild inflammatory infiltrate and foamy, eosinophilic intraalveolar fluid. Organisms are typically not discernible without special stains. (Right) Histologic section from lung with pneumocystis is shown by GMS. With the silver stain, the organisms appear as circular, crescentic, and cup-shaped gray to black 5 m cysts.

(Left) This coronal section of brain is taken from a patient dying with CNS cryptococcus. Destructive, cystic lesions appear in the basal ganglia. Cryptococcus produces a thick polysaccharide capsule, and the gross lesions may appear gelatinous, as in this case. (Right) Image shows an acidfast stain of small bowel with MAC. AIDS patients often cannot form granulomas. Routine H&E sections may show only foamy histiocytes, but acid-fast stains will show numerous organisms.

(Left) Typical viral cytopathic effect of cytomegalovirus (CMV) is shown on H&E . Note the large size (compared to surrounding inflammatory cells) of the infected cell, its prominent "owl’s-eye" intranuclear inclusion, and the smaller intracytoplasmic inclusions. (Right) HSV-infected cells from esophagus are shown on H&E. A cell with typical herpetic viral cytopathic effect can be seen. The affected cell is enlarged and multinucleated with "ground-glass" nuclei and nuclear molding.

Disease Process Approach to Autopsy: Infection-Related Death

HIV/AIDS

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Disease Process Approach to Autopsy: Infection-Related Death

SHOCK AND SEPSIS

This image shows ischemic necrosis of the fingertips with proximal edema and erythema as a result of prolonged, severe shock.

TERMINOLOGY Abbreviations

Systemic inflammatory response syndrome (SIRS) Multiple organ dysfunction syndrome (MODS)

Synonyms

MODS: Multi-organ failure, multiple systems organ failure

Definitions

Shock: Inability to meet cellular metabolic

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requirements due to global hypoperfusion from inadequate circulating blood or plasma volume MODS: Physiologic dysfunction of 2 organ or physiologic systems not directly related to primary cause of shock e.g., acute tubular injury and coagulopathy following cardiogenic shock due to acute myocardial infarction SIRS: Systemic activation of innate immune response, regardless of cause, clinically manifested as 2 or more of the following Temperature > 38C or < 36C; heart rate (HR) > 90 beats/min; hyperventilation (respiratory rate > 20 breaths/min or PaCO < 32mmHg); white blood cell (WBC) count > 12,000/L or < 4,000/L or 10% bands Sepsis: Probable or documented infection plus SIRS manifestations Severe sepsis: Sepsis plus infection-induced organ dysfunction, tissue hypoperfusion, or hypotension Organ dysfunction: Altered mental status, generalized edema, acute lung injury, acute renal injury, oliguria, edema, coagulopathy, hyperbilirubinemia, hyperglycemia, ileus, thrombocytopenia Tissue hypoperfusion: Lactate > 1mmol/L, capillary refill, or mottling

The subendocardium in this autopsy heart section shows early ischemic changes of hypereosinophilia and wavy myocytes due to prolonged shock (demand ischemia).

Hypotension: Systolic blood pressure (BP) < 90mmHg or mean arterial pressure < 70mmHg Septic shock: Sepsis plus hypotension persisting despite administration of adequate fluid resuscitation Stigmata of shock: Nonspecific pathologic findings reflecting pattern of organ injury due to tissue hypoperfusion

ETIOLOGY/PATHOGENESIS Causes of Shock

Hypovolemic: Massive loss of blood or plasma volume e.g., hemorrhage, burns, massive vomiting or diarrhea, anaphylaxis Cardiogenic: Inability of heart to pump blood due to intrinsic failure (e.g., infarction, arrhythmia, cardiomyopathy) or external factors (e.g., cardiac tamponade, pulmonary embolism, tension pneumothorax)

Pathogenesis of Shock

Initial phase: tissue perfusion sympathetic nervous system activation HR, myocardial contractility, arterial & venous tone; activation of renin-angiotensin system BP maintained with blood preferentially shunted to heart & brain Progressive phase: BP & tissue perfusion global tissue hypoxia, lactic acid, pH arteriolar dilation, venous constriction, capillary permeability loss of intravascular volume organ dysfunction Irreversible phase: Refractory hypotension, multiple system organ failure, and death

Causes of SIRS

Overwhelming microbial infection or release of microbial toxins Deaths due to sepsis: Gram negative bacteria > Gram positive bacteria > fungal >> opportunistic bacteria & fungi, viruses

Key Facts Terminology

Shock: Inability to meet cellular metabolic requirements due to inadequate circulating blood or plasma volume MODS: Physiologic dysfunction of 2 organ or physiologic systems not directly related to primary cause of shock SIRS: Systemic activation of innate immune response, regardless of cause Sepsis: Probable or documented infection plus SIRS manifestations

Etiology

Shock: Hypovolemic, cardiogenic, systemic inflammation

SIRS: Sepsis, massive tissue injury, metabolic

Macroscopic Pathology

Evidence of specific cause of shock Macroscopic stigmata of shock: e.g., diffuse petechia, pallor, edema, serosal effusions, "nutmeg" liver

Microscopic Pathology

Shock: Diffuse vascular congestion, hemorrhage, fibrin thrombi of microvasculature involving any organ system Sepsis: Evidence of primary infection, septic emboli to any organ, widespread bacterial overgrowth Microscopic stigmata of shock: e.g., subendocardial demand ischemia, diffuse alveolar damage, hepatic centrilobular hemorrhagic necrosis, acute tubular necrosis

derangements, malignancy, neurologic trauma

Tissue injury: Massive trauma, severe burns, surgery, ischemia/reperfusion injury, transplant rejection, pancreatitis, erythroderma Metabolic: Thyroid storm, acute adrenal insufficiency Therapy related: Blood products, granulocytemacrophage colony-stimulating factor, anesthesiarelated malignant hyperpyrexia, neuroleptic malignant syndrome, opiates, benzodiazepines Malignancy: Lymphoma, tumor lysis syndrome Neurologic: Subarachnoid hemorrhage

Incidence and number of deaths increasing in USA and worldwide

Presentation

Shock: Varies with etiology; most common clinical manifestations are hypotension, tachycardia, cyanosis, and evidence of organ dysfunction Sepsis: Most common primary sites of infection (in frequency) are lung, bloodstream, abdomen, skin and soft tissue, urinary tract, and central nervous system

Predisposing Factors to SIRS

Treatment

immune system Age ( risk neonates & elderly)

Prognosis

Inherited or acquired defects in innate or adaptive

Pathogenesis of SIRS

Systemic activation of innate immune response

Activation of neutrophils, monocytes/macrophages, & endothelium Early phase: Excessive pro-inflammatory cytokines release vasodilation, edema Late phase: Diminished innate immune function

diminished adaptive immune function Pro-oxidant state: reactive oxygen & nitrogen species, free radical scavengers vasodilation, edema Pro-coagulation state: Complement, coagulation cascade, & endothelial activation disseminated intravascular coagulation (DIC) metabolic derangements, organ dysfunction, and shock

Shock: Identify and treat underlying cause Sepsis: Supportive therapy only Mortality rate of shock: Varies according to severity and etiology

Mortality rate of sepsis:

Average: 20-30%; range: 5-50% Varies according to predisposing factors, degree of organ dysfunction, type and site of infectious agent

Clinical Organ Dysfunction Scoring Systems

Commonly used scoring systems for assessing severity of illness and predicting mortality in ICU patients General prognostication scores: Acute physiology and chronic health evaluation (APACHE), simplified acute physiology score (SAPS), mortality probability models (MPM) Organ dysfunction scores: Sequential organ failure assessment (SOFA), multiple organ dysfunction score (MODS), logistic organ dysfunction system (LODS)

CLINICAL ISSUES

IMAGE FINDINGS

Epidemiology

Radiographic Findings

SIRS: Most critically ill patients meet criteria Sepsis: Most common cause of death in noncoronary intensive care unit (ICU) 600,000 cases annually in USA

Disease Process Approach to Autopsy: Infection-Related Death

SHOCK AND SEPSIS

Lungs: Diffuse bilateral infiltrates ("white out")

Ultrasonographic Findings

Heart: Systolic and diastolic ventricular dysfunction

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Disease Process Approach to Autopsy: Infection-Related Death

SHOCK AND SEPSIS

CT Findings

Brain: Hypodensities in bilateral watershed areas progressing to whole brain edema

Other: Evidence of specific underlying cause of shock &/or sepsis

External Examination

Laboratory Tests

Extensive petechia &/or ecchymoses Pallor of conjunctiva &/or nailbeds Cyanosis of distal extremities Severe peripheral edema Jaundice

Internal Examination

Evidence of specific cause of shock such as massive acute myocardial infarction, gastrointestinal hemorrhage, perforated viscus with fecopurulent exudate Macroscopic stigmata of shock Soft tissue edema &/or hemorrhage Serous effusions Brain: Diffuse cerebral swelling uncal or cerebellar herniation Lungs: Firm, heavy, wet hemorrhage, frothy fluid within airways Heart: Epicardial &/or endocardial petechia, acute subendocardial ischemia Liver: Mottled cut surface ("nutmeg" appearance) Pancreas: Fat saponification Gastrointestinal tract: Serosal and mucosal petechia, mucosal erosions Kidneys: Cortical pallor with medullary congestion

Shock: Diffuse vascular congestion, hemorrhage, fibrin thrombi of microvasculature involving any organ system Sepsis: Evidence of primary infection (e.g., acute bronchopneumonia, meningitis), septic emboli to any organ (highly specific), widespread bacterial overgrowth disproportional to postmortem interval

Organ Examination

Microscopic stigmata of shock

Histochemistry

GMS (Gomori methenamine silver) Gram

Histologic Features

ANCILLARY TESTS

MACROSCOPIC FEATURES

MICROSCOPIC PATHOLOGY

III

Spleen: Acute splenitis, congestion Bone marrow: Reactive hypercellularity Adrenal glands: Cortical cell lipid depletion, microscopic foci of hemorrhage within cortex

Low ejection fraction is predictor of mortality in septic shock

Brain: Hypoxic nerve cell change, cerebritis (sepsis) Heart: Subendocardial ischemia (demand ischemia) Lungs: Alveolar edema, capillary congestion, diffuse alveolar damage Liver: Centrolobular hemorrhagic necrosis, canalicular or ductal cholestasis, steatosis Gastrointestinal tract: Submucosal hemorrhages, erosions, or ulcerations Kidneys: Acute tubular necrosis, pigmented casts (hemoglobin, myoglobin, or bile)

Supporting evidence of organ dysfunction (if antemortem samples not available) e.g., troponin level, CBC, chemistry panel Postmortem blood cultures: High false positive rate due to agonal bacteremia, postmortem bacterial transmigration Positive postmortem blood cultures should correlate with gross and histologic evidence of infection

Specialty Consultation

Centers for Disease Control and Prevention Infectious Diseases Pathology Branch Provides important information and guidelines related to transport of pathology materials and clinical samples for ancillary testing

SELECTED REFERENCES 1.

4. 5.

Centers for Disease Control and Prevention: Specimen Submission Guidelines. http://www.cdc.gov/ncezid/dhcpp/ idpb/specimen-submission/index.html. Updated May 7, 2015. Accessed June 22, 2014 Dellinger RP et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 39(2):165-228, 2013 Orsini J et al: Microbiological profile of organisms causing bloodstream infection in critically ill patients. J Clin Med Res. 4(6):371-7, 2012 Vincent JL et al: Clinical review: scoring systems in the critically ill. Crit Care. 14(2):207, 2010 Neely WA et al: Septic shock: clinical, physiological, and pathological survey of 244 patients. Ann Surg. 173(5):657-66, 1971

Gross, Radiographic, and Microscopic Features (Left) At autopsy, this brain demonstrated severe cerebral edema with swollen, flattened gyri and narrowed sulci . Cerebellar tonsil herniation was also present (not shown). (Right) This is the cerebrum of the same patient with diffuse hypoxic nerve cell change . The neurons are shrunken and triangular.

(Left) These lungs from a patient dying of H1N1 influenza were profoundly edematous and congested (weight was 4x upper limit normal). There was widespread diffuse alveolar damage of 1 week duration present microscopically. (Right) This chest xray of the same patient demonstrates diffuse bilateral infiltrates (white-out). The costovertebral angles and cardiac silhouette are difficult to visualize due to the infiltrates.

Disease Process Approach to Autopsy: Infection-Related Death

SHOCK AND SEPSIS

(Left) The microscopic features of diffuse alveolar damage of less than 1 week duration are shown here, including hyaline membrane formation and intraalveolar hemorrhage . (Right) Diffuse alveolar damage of greater than 1 week duration is seen in this image, with resolution of the acute changes with extensive type II pneumocyte hyperplasia along the alveoli . Marked interstitial fibrosis may result as well (not shown here).

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Disease Process Approach to Autopsy: Infection-Related Death

SHOCK AND SEPSIS

Gross and Microscopic Features (Left) Diffuse petechiae of the skin are a frequent finding in patients dying of shock due to terminal coagulopathy. (Right) The visceral and parietal serosa also frequently demonstrated petechial hemorrhages in coagulopathy associated with shock and sepsis.

(Left) This pancreas contained numerous thrombi of the microvasculature in a patient dying of disseminated intravascular coagulation. Other organs involved included the heart, lungs, and adrenal glands. An uninvolved, patent venule is also shown for comparison . (Right) This autopsy heart, opened through the tricuspid valve to view the right atrium and ventricles, shows multiple friable vegetations on the closing surface and cords of the valve (bacterial endocarditis).

(Left) This photomicrograph of the heart with a right atrial subendocardial abscess shows neutrophilic inflammation and bacterial colonies . Normal myocardium is seen at the lower left for reference. (Right) This photomicrograph of the lung from the same patient with right atrial abscess shows a septic embolus in a pulmonary artery branch.

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Gross and Microscopic Features (Left) A perforation in the small bowel in this patient caused acute peritonitis with fecopurulent fluid within the peritoneal cavity, ultimately leading to septic shock and death. (Right) The dark black discoloration of the distal small bowel and colon is due to a massive lower gastrointestinal bleed, which caused the patient to exsanguinate. The lumen contained dark liquid blood .

(Left) The variegated, "nutmeg" appearance of the cut surface of the liver is due to passive congestion from a lack of adequate forward flow blood circulation. (Right) This photomicrograph from the same liver shows centrilobular hemorrhagic necrosis and ductal cholestasis microscopically.

Disease Process Approach to Autopsy: Infection-Related Death

SHOCK AND SEPSIS

(Left) These severely mottled kidneys are from a patient dying of hemorrhagic shock due to a dissecting aortic aneurysm originating in the thoracic aorta. The true lumen and false lumen of the aorta are shown, with a medial flap separating them. (Right) This kidney shows acute tubular necrosis (ATN) with dilated proximal tubules . Autolysis often precludes definitive evaluation of the nuclear and cytoplasmic changes of ATN.

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Disease Process Approach to Autopsy: Infection-Related Death

BRONCHOPNEUMONIA

This gross photograph of a lung shows bronchopneumonia with foci of consolidation centered on the airway and often most pronounced in the basilar regions.

TERMINOLOGY

Foci of bronchopneumonia are typically 1-3 cm in diameter and poorly circumscribed .

of peribronchial/peribronchiolar alveolated parenchyma

Definitions

Pneumonia is classified by specific etiologic agent;

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however, if no pathogen can be isolated, clinical setting in which infection occurs is used as a guide for therapy Community-acquired pneumonia (CAP): Pneumonia acquired outside of health care setting Most common type of pneumonia incidence in winter ~ 20% of patients with CAP will require hospitalization Up to 50% of CAP have no pathogen identified Atypical Pneumonia: Old terminology for CAP with milder symptoms, scant sputum, and lack of response to penicillin Hospital-acquired pneumonia: Acquired while in hospital for another illness (synonym: Nosocomial pneumonia) Patients tend to be sicker due to underlying illness risk of antibiotic-resistant bacteria Health care-associated pneumonia: Acquired in a nonhospital health care setting such as nursing home, dialysis center, outpatient clinic Pathologic definition of bronchopneumonia is based on anatomic distribution of acute inflammatory changes Pathologic changes can be appreciated grossly as patchy foci of airway-centered consolidation with intervening areas of normal lung parenchyma (lobular distribution) This lobular pattern is in contrast to lobar pneumonia, which is consolidation of an entire lobe Pathologic changes can be appreciated microscopically as foci of airway-centered inflammation with contiguous involvement

ETIOLOGY/PATHOGENESIS Pathogenesis

Microorganisms reach lung by 4 basic mechanisms

Inhalation Aspiration (primarily from a previously colonized oropharynx) Hematogenous spread Direct extension from an adjacent focus of infection In most circumstances, pathologic entity of bronchopneumonia is result of inhalation and aspiration Endotracheal tube placement further compromises host defenses by impairing mucociliary function, injuring mucosa, and allowing secretions to pool More likely in patients with other comorbidities More common in patients with an impaired immune response (due to immunosuppressive medications, underlying immunodeficiency disease, or critical illness) More common with a large inoculum (such as occurs with massive aspiration) More common in patients with genetic differences, which are a focus of ongoing research A preceding viral pneumonia increases susceptibility to bacterial pneumonia

Infectious Agents Bacteria

Gram positive: Staphylococcus aureus, Streptococcus pneumoniae (most common cause of lobar pneumonia) Gram negative: Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Legionella pneumophila, Pseudomonas aeruginosa, Klebsiella pneumoniae

Key Facts Terminology

Pathologic definition of bronchopneumonia based on anatomic distribution of acute inflammatory changes Distribution can be appreciated grossly as patchy foci of airway-centered consolidation with intervening areas of normal lung parenchyma (lobular distribution) Lobular pattern is in contrast to lobar pneumonia (consolidation of an entire lobe) Pneumonia is classified by specific etiologic agent

Etiology

Most often result of inhalation of microorganisms or aspiration A preceding viral pneumonia increases susceptibility to secondary infection (bronchopneumonia)

Gram-negative organisms predominate in ICUacquired infections and ventilator-associated pneumonia, particularly P. aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae Viruses and fungal organisms can cause bronchopneumonia, mainly in immunocompromised patients Herpes viruses, Candida spp, and Aspergillus spp most common Agents associated with community-acquired "atypical pneumonia" include Bacteria: Mycoplasma pneumoniae, Legionella spp., Chlamydia spp., Coxiella burnetii Viruses: Respiratory syncytial virus, adenovirus, and influenzas A and B Progressive primary pulmonary tuberculosis can resemble an acute bacterial pneumonia

CLINICAL ISSUES Epidemiology Incidence

Only a small percentage of those patients requiring hospitalization for CAP will die, usually of complications related to pneumonia (such as empyema, meningitis, or endocarditis) or because of a debilitated state Nosocomial pneumonia: 2nd most common cause of nosocomial infection and leading cause of death from hospital-acquired infection Mechanical ventilation is the leading risk factor for development of nosocomial pneumonia Age Very young and elderly are more susceptible than other patient populations

Presentation

Shortness of breath, fever, productive cough, malaise, and pleuritic chest pain

Nosocomial pneumonia is leading cause of death from hospital-acquired infection

Gram-negative organisms predominate in ICUacquired infections and ventilator-associated pneumonia

Macroscopic Pathology

May involve 1 or multiple lobes and is frequently bilateral

Most pronounced changes often in basilar regions

Microscopic Pathology

Airway-centered acute inflammation with contiguous involvement of peribronchial/peribronchiolar alveolated parenchyma Focal or extensive organization may be present

Laboratory Tests

Check premortem sputum and blood culture results Elevated WBC with left shift and bands (low WBC in patients who have underlying neutropenia and sometimes with severe infection) Thrombocytopenia, elevated fibrin degradation products (sepsis, DIC) Cold agglutinins: Not specific for Mycoplasma but if high titer cold agglutinin (> 1:64) in CAP = high likelihood of mycoplasma Increased liver function tests and elevated creatinine (organ system injury from sepsis/shock) and lactic acid (shock) Serologic evidence of infection: Paired sera to look for antibodies to Mycoplasma, Chlamydia influenza A and B, adenovirus, and respiratory syncytial virus Being replaced by more specific and rapid PCR techniques for organism isolation Legionella urine antigen test

Disease Process Approach to Autopsy: Infection-Related Death

BRONCHOPNEUMONIA

Prognosis

Patients with healthcare-acquired pneumonia (HCAP) typically have a worse clinical course and outcome than those of patients with CAP Patients developing necrotizing pneumonia usually have concomitant medical illness, most common being diabetes mellitus and alcohol abuse

IMAGE FINDINGS Radiographic Findings

Multifocal, heterogeneous opacities distributed along course of airways and centered in distal airways

MACROSCOPIC FEATURES External Examination

Signs of treatment: Endotracheal tube, chest tube (empyema, parapneumonic effusion), central and peripheral intravenous lines

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Disease Process Approach to Autopsy: Infection-Related Death

BRONCHOPNEUMONIA Chest radiograph prior to autopsy may indicate placement of endotracheal tube, chest tube, presence of effusion, empyema, central line placement Follow radiologic safety precautions: Leave room during x-ray procedure if performed in autopsy suite Signs of sepsis/shock: Petechiae (DIC), jaundice, pallor

Acute bronchitis: Neutrophil-rich suppurative exudate within lumen, and mucosal ulceration/ necrosis Acute pneumonia involving peribronchial/ peribronchiolar alveolated parenchyma Neutrophil-rich intraalveolar fibrinous exudate and active capillary congestion Depending on time course of infection and effectiveness of therapy, focal or extensive organization may be present It is not uncommon in patients with a protracted hospital course to see evidence of multiple episodes of infection, with acute inflammation in 1 region and more advanced organizing pneumonia in others Organizing pneumonia: Polypoid accumulation of granulation tissue in alveolar spaces, ducts, and sometimes in bronchioles

in addition to frank empyema

Fresh lung and spleen tissue should be procured for microbiology cultures before excessive organ manipulation Culture technique: Use sterile equipment (scalpel, forceps), sterilize pleural or capsular surface of organ with either heat (hot spatula or scalpel blade used to sear surface) or iodine and alcohol decontamination of surface Use sterile container for transport to microbiology lab Follow safety precautions if using heat source, check with safety engineers prior to using, and use flame retardant gloves Use universal precautions for all pneumonia autopsies: Personal protective equipment and particulate respirators Look for evidence of bacteremic dissemination to other organs

1 or multiple lobes and is frequently bilateral Most pronounced changes are often in basilar regions Foci of consolidation are centered on airway and are typically 1-3 cm in diameter, poorly circumscribed, and yellow to gray-red in color Consolidation is best appreciated following formalin perfusion Foci of consolidation can expand to near confluence, thereby mimicking lobar pneumonia Gross description should include distribution of consolidated areas as well as complications of pneumonia, such as prominent necrosis (necrotizing pneumonia) and abscess formation Section adequately to document distribution of disease, areas of necrosis or abscess, and noninvolved lung parenchyma Other organs Sepsis/shock changes: Pallor of renal cortex (acute tubular injury), softening of liver (shock liver), Ischemic bowel (shock) Disseminated Infection: Vegetations on cardiac valves, disseminated abscesses Cause for underlying immunosuppression: Malignancy, transplantation, etc.

Respiratory system

Acute pleuritis and fibrinous adhesions may be present

Respiratory System: Bronchopneumonia may involve

Histologic Features

Internal Examination

Organ Examination

III

MICROSCOPIC PATHOLOGY

ANCILLARY TESTS Histochemistry

Tissue gram, silver, PAS, mucicarmine or acid-fast/ modified acid-fast stains as appropriate

Immunohistochemistry

Immunohistochemical stains for microorganisms as appropriate

In Situ Hybridization

In situ hybridization for microorganisms as appropriate

Microbiology

Tissue culture procured in sterile fashion Molecular diagnostic tests, as appropriate

DIFFERENTIAL DIAGNOSIS Processes That Mimic Gross Consolidation Pulmonary hemorrhage Diffuse alveolar damage

SELECTED REFERENCES 1. 2. 3. 4.

DiBardino DM et al: Aspiration pneumonia: A review of modern trends. J Crit Care. Epub ahead of print, 2014 Wunderink RG et al: Community-acquired pneumonia. N Engl J Med. 370(19):1863, 2014 Nair GB et al: Nosocomial pneumonia: lessons learned. Crit Care Clin. 29(3):521-46, 2013 Peleg AY et al: Hospital-acquired infections due to gramnegative bacteria. N Engl J Med. 362(19):1804-13, 2010

Gross and Microscopic Features (Left) More confluent areas of bronchopneumonia are pictured here . These areas are paler than the surrounding parenchyma and will feel firmer than the adjacent lung tissue on palpation (consolidation). (Right) Gross image shows fungal bronchopneumonia (Aspergillus spp.). Aspergillus is vasoinvasive and although not demonstrated here, may show a targetoid appearance with consolidation surrounding a central thrombosed vessel.

(Left) Fibrinous pleural adhesions are illustrated in this gross image of a patient who had pneumonia with a parapneumonic effusion. The fibrinous strands coursing between visceral and parietal pleura are easily disrupted, as opposed to fibrous adhesions. (Right) Abscess cavity formation is a major complication of bronchopneumonia. The necrotic material in the center has fallen out and we see the edge of the cavity surrounded by white fibrous tissue .

Disease Process Approach to Autopsy: Infection-Related Death

BRONCHOPNEUMONIA

(Left) Neutrophils and fibrin fill the alveolar spaces in this example of acute pneumonia with congestion . (Right) This example of acute pneumonia was ultimately cultureproven as Mycobacterium tuberculosis. Note the single giant cell in the center but the lack of a well-organized granulomatous response in an early primary infection. Universal precautions must be used during autopsies on patients with pneumonia.

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Disease Process Approach to Autopsy: Infection-Related Death

INFECTIVE ENDOCARDITIS

This autopsy heart shows a large pedunculated vegetation involving the tricuspid valve. The vegetation appears to arise at a septal leaflet commissure.

TERMINOLOGY Definitions

Inflammation of endocardium (typically refers to infections on valve surfaces)

ETIOLOGY/PATHOGENESIS Infectious Agents

Staphylococcus aureus (31%) Streptococcus viridans (17%) Coagulase-negative staphylococci (11%) Enterococci (11%) Other streptococci (12%) Gram-negative HACEK (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella species) (2%)

Gram-negative non-HACEK (2%)

Risk Factors

Microbe portal of entry

Intravenous drug abuse Indwelling catheter Hemodialysis Dental procedure Valve surface damage Degenerative Congenital Rheumatic

CLINICAL ISSUES Presentation

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3-10 episodes per 100,000 person-years Mean age: 51-65 years M > F 1.2-2.5:1 Hospital mortality rate 9.6-26% Acute Distant septic emboli

A tissue Gram stain from this vegetation shows grampositive cocci , the most common type of bacteria seen in endocarditis. Necrotic debris, fibrin, and inflammation are also seen.

Acute valvular insufficiency

Subacute

Duke criteria Positive blood culture (2 separate draws) Positive imaging study (vegetation by echocardiogram, abscess by CT, etc.) Minor criteria: Predisposition, fever, emboli, glomerulonephritis

Treatment

Antibiotic therapy (intravenous) often followed by surgery several weeks later

Prosthetic Valve Endocarditis

More common in people whose native valves had infective endocarditis Often with same organism Commonly occurs within 2 years of replacement (incidence 16%) Presentation Paravalvular leak Valve sewing ring abscess Dehiscence Obstructive vegetation

IMAGE FINDINGS Echocardiography

Vegetations Regurgitant jets (Doppler) Abscesses Prosthetic valve dehiscence

MACROSCOPIC FEATURES External Examination

Splinter hemorrhages under fingernails

Key Facts Terminology

Infective endocarditis: Inflammation of endocardium

Macroscopic Pathology Vegetations

Fleshy, soft, clot-like, friable Septic emboli and infarcts (brain, spleen, kidneys, liver)

(typically refers to infections on valve surfaces)

Etiology

Staphylococcus aureus (31%) Streptococcus viridans (17%) Microbe portal of entry

Intravenous drug abuse, dental procedure Valve surface damage Degenerative, rheumatic, congenital

Clinical Issues

3-10 episodes per 100,000 person-years Mean age: 51-65 years M > F (1.2-2.5:1) Hospital mortality rate 9.6-26% Janeway lesions: Flat macules, especially on hands and

Microscopic Pathology Vegetations

Acute: Fibrin, platelets, neutrophils, microorganisms Subacute: Granulation tissue, fibroblasts, collagen, plasma cells, absent microbes Valve annulus abscess Myocardial abscess

Top Differential Diagnoses

Nonbacterial thrombotic endocarditis Specific types

Marantic: Associated with malignancy Libman-Sacks: Associated with lupus, other autoimmune disease

feet Osler nodes: Red raised lesions of hands and feet Conjunctival hemorrhage

Heart Findings Vegetations

Typically atrial aspect of atrioventricular valves and ventricular aspect of semilunar valves Fleshy, soft, clot-like, friable Ruptured cordae Leaflet perforation Cusp aneurysm (old healed endocarditis) Infraction (septic emboli to coronary arteries) Perivalvular (ring) abscess

SELECTED REFERENCES 1.

2. 3.

Extracardiac Findings

Septic emboli and infarcts (brain, spleen, kidneys, liver) Mycotic (pseudo) aneurysms Glomerulonephritis (endocarditis-associated postinfectious type) Secondary infection of abdominal aortic aneurysm

MICROSCOPIC PATHOLOGY Histologic Features Vegetations

Disease Process Approach to Autopsy: Infection-Related Death

INFECTIVE ENDOCARDITIS

5. 6.

Erdozain JG et al: Cardiac valve replacement in patients with antiphospholipid syndrome. Arthritis Care Res (Hoboken). 64(8):1256-60, 2012 Asopa S et al: Non-bacterial thrombotic endocarditis. Eur J Cardiothorac Surg. 32(5):696-701, 2007 Aryana A et al: Nonbacterial thrombotic endocarditis with recurrent embolic events as manifestation of ovarian neoplasm. J Gen Intern Med. 21(12):C12-5, 2006 Edoute Y et al: Cardiac valvular vegetations in cancer patients: a prospective echocardiographic study of 200 patients. Am J Med. 102(3):252-8, 1997 Lopez JA et al: Nonbacterial thrombotic endocarditis: a review. Am Heart J. 113(3):773-84, 1987 Deppisch LM et al: Non-bacterial thrombotic endocarditis: clinicopathologic correlations. Am Heart J. 92(6):723-9, 1976 MACDONALD RA et al: The significance of nonbacterial thrombotic endocarditis: an autopsy and clinical study of 78 cases. Ann Intern Med. 46(2):255-73, 1957 Allen AC et al: The morphogenesis and significance of degenerative verrucal endocardiosis (terminal endocarditis, endocarditis simplex, nonbacterial thrombotic endocarditis). Am J Pathol. 20(6):1025-55, 1944

Acute: Fibrin, platelets, neutrophils, microorganisms Subacute: Granulation tissue, fibroblasts, collagen, plasma cells, absent microbes Tendinous cord and leaflet destruction, erosion Valve annulus abscess Myocardial abscess

DIFFERENTIAL DIAGNOSIS Nonbacterial Thrombotic Endocarditis Fibrin, platelets, without bacteria or purulent

inflammation Typically, small, dotting closing surfaces of leaflets

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Disease Process Approach to Autopsy: Infection-Related Death

INFECTIVE ENDOCARDITIS

Gross Features (Left) This autopsy heart shows a friable vegetation associated with the mitral valve. Significant left ventricular hypertrophy and mitral annular calcification are also present in this elderly person (unrelated to endocarditis). (Right) Endocarditis can involve other nonvalvular endocardial surfaces also, such as this right atrial vegetation associated with an infected catheter tip. The metal probe passes under the thebesian valve of the coronary sinus ostium .

(Left) Endocarditis can also involve prostheses, such as this valved conduit specimen. The texture of the vegetation is similar to thrombus and is often crumbly and friable. Embolic potential of masses like this is obvious. (Right) The leaflets of this Melody valve prosthesis have been perforated and eroded by active endocarditis. The cusp edges show fleshy, friable, pink vegetative material.

(Left) This congenitally malformed aortic valve was secondarily infected. Old healed endocarditis has resulted in persistent leaflet perforation that would have resulted in significant valvular incompetence. The leaflet shows significant thickening due to fibroelastosis, consistent with postinflammatory disease. (Right) Lambl excrescences , as seen on this aortic valve cusp, are normal anatomic variants and should not be mistaken for endocarditis.

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Microscopic Features (Left) "Colonies" or clusters of bacterial organisms can often be seen well on the H&E stain alone in active endocarditis. Gram staining is needed to assess the Gram reaction. After prolonged antibiotic treatment, they may be harder to appreciate. (Right) Tissue Gram staining is helpful in narrowing the diagnosis to a particular class of microbes (in this case, gram-positive cocci ). Organisms are more likely to be identified in the absence of antibiotic treatment.

(Left) Fungal endocarditis is most commonly due to Candida species. The yeast forms in Candida infections show both budding and pseudohyphae . Candida vegetations are typically very bulky and obstructive. (Right) This tissue Gram stain of an endocarditis vegetation demonstrates gram-positive rods , such as may be seen in infections due to Erysipelothrix or Nocardia.

(Left) In cases of subacute or healing endocarditis, there may be a predominance of plasma cells and macrophages rather than neutrophils. Organisms are rarely present at this stage of endocarditis. (Right) This elastic-stained mitral leaflet shows vegetative material on both sides of the valve. Classically, endocarditis is destructive and disrupts the normal trilaminar architecture of the valves. Evidence of destruction persists after healing and may be a helpful clue.

Disease Process Approach to Autopsy: Infection-Related Death

INFECTIVE ENDOCARDITIS

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CLOSTRIDIUM DIFFICILE ENTEROCOLITIS

This colonic mucosa is covered with small to confluent pseudomembranes. They are green-yellow and focally lift off of the mucosal surface .

TERMINOLOGY Synonyms

Pseudomembranous enterocolitis or colitis, Clostridium difficile-associated disease (CDAD), antibiotic or clindamycin-associated colitis

Definitions

Colitis due to toxins of C. difficile organism

ETIOLOGY/PATHOGENESIS Infectious Agents C. difficile

Anaerobic gram-positive spore-forming bacterium Dormant spore form resistant to antibiotics/heat; may remain in environment for months to years Vegetative (nondormant), toxin-producing form Fastidious; "difficile" derived from difficulty growing organism in culture

Pathogenesis

Altered gut flora colonization (usually nosocomial), fecal-oral Host factors + organism virulence disease Disease due to effects of toxins A and B A: Enterotoxin: Marked fluid exudation from bowel B: Cytotoxin: Affects actin polymerization Hypervirulent NAP-1 strain virulence renal failure toxic megacolon

CLINICAL ISSUES Epidemiology

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Incidence

Age-adjusted death rate: 2.4/100,000 in standard population (2011) 9.1% from 2010

A pseudomembrane of Clostridium difficile enterocolitis is classically mushroom shaped. Abrupt transition from normal to affected mucosa is also characteristic.

17th leading cause of death in patients 65 years of age (2011) Age More common in older individuals ( 60 years) Risk factors Age, hospitalization (prolonged or intensive care unit), prior CDAD, current or prior antibiotic use, underlying severe illness, immunosuppression (solid organ and bone marrow transplant patients susceptible to severe disease), bypass of gastric acid (medications or enteral feeds)

Presentation

Diffuse watery diarrhea, abdominal pain, fever Acute renal failure, sepsis, and shock progressing to death

Uncommon extraintestinal symptoms

Large joint arthritis, osteomyelitis, and splenic abscess

Laboratory Tests

Leukocytosis and elevated creatinine Electrolyte disturbances (dehydration), albumin (protein-losing enteropathy), lactate (septic shock)

Enzyme immunoassay for toxins A and B and PCR for C. difficile toxin gene

IMAGE FINDINGS Radiographic Findings

Nodular haustral thickening Dilated colon, ileus, pneumatosis (severe disease)

CT Findings

Thickened bowel wall (most common finding), mild pericolonic stranding

Key Facts Etiology

Microscopic Pathology

nosocomial), fecal-oral Host factors + organism virulence disease Disease due to effects of toxins A and B A: Enterotoxin: Marked fluid exudation from bowel B: Cytotoxin: Affects actin polymerization

surrounded by normal-appearing mucosa Dilated crypt erupts into bowel lumen as pseudomembrane Epithelial cells lining involved crypts are necrotic Inflammation is superficial in crypts and pseudomembrane Pseudomembrane composed of mucus, neutrophils, fibrin and necrotic epithelium Severe disease has mucosal necrosis and deep mural inflammation Other organ changes Sepsis-related acute tubular injury, patchy hepatic necrosis

Altered gut flora colonization (usually

Macroscopic Pathology

Changes due to prolonged severe diarrhea, colitis, and protein-losing enteropathy

Dehydration changes (skin tenting, sunken eyes), raw-appearing anal tissue with possible tissue breakdown, often with decubitus ulcer Distended abdomen Generalized edema (anasarca)

MACROSCOPIC FEATURES External Examination

Sepsis changes: Petechiae, secondary acrocyanosis, jaundice Surgical intervention: Laparotomy incision ostomy Changes due to prolonged severe diarrhea and colitis and protein-losing enteropathy Dehydration (skin tenting, sunken eyes), rawappearing anal tissue with possible tissue breakdown, possible decubitus ulcer Distended abdomen, anasarca

Internal Examination

Serous ascites (protein loss), fibrinopurulent ascites

Patchy process involving clusters of crypts

Lamina propria intact (no ischemia) Severe disease: Mucosal necrosis and deep mural inflammation

Other organs: Acute tubular necrosis, patchy hepatic necrosis, subendocardial ischemia, heart failure (usually underlying coronary artery/ischemic heart disease)

DIFFERENTIAL DIAGNOSIS Pseudomembranous Colitis

Nonantibiotic drug-induced colitis (chlorpropamide, NSAIDs)

Colitis caused by other organisms: Verotoxinproducing Escherichia coli, Staphylococcus aureus

(toxic megacolon, perforation) Dusky, dilated colon (if toxic megacolon) Surgical bowel anastomosis ostomy

REPORTING CRITERIA

Organ Examination

Final Report

Bowel wall edema; mucoid, liquid, sometimes bloodspeckled bowel content Green-yellow pseudomembranes 2-10 mm in early disease Confluent, with ulcerated mucosa, severe disease Splenic abscess: Rare extraintestinal manifestation Pallor of renal cortex (acute tubular injury), patchy hepatic necrosis (shock)

MICROSCOPIC PATHOLOGY Histologic Features

Patchy process: Affected crypts, intervening normalappearing mucosa

Dilated crypt erupts into bowel lumen as pseudomembrane Epithelial cells lining involved crypts are necrotic Inflammation is superficial in crypts and pseudomembrane Pseudomembrane composed of mucus, neutrophils, fibrin, and necrotic epithelium

Disease Process Approach to Autopsy: Infection-Related Death

CLOSTRIDIUM DIFFICILE ENTEROCOLITIS

Presence of C. difficile colitis (after ruling out other causes of pseudomembranous colitis), severity of disease, associated findings (shock, etc.) State whether it was cause of death, contributing factor, or incidental Risk factors for developing disease Severe underlying illness, transplantation, clinical history of prior antibiotic therapy Implication of finding Unsuspected disease in hospitalized patient warrants institutional infection control notification to avoid spread of disease

SELECTED REFERENCES 1.

Hurley BW et al: The spectrum of pseudomembranous enterocolitis and antibiotic-associated diarrhea. Arch Intern Med. 162(19):2177-84, 2002 Totten MA et al: Clinical and pathological spectrum of antibiotic-associated colitis. Am J Gastroenterol. 69(3 Pt 1):311-9, 1978

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CLOSTRIDIUM DIFFICILE ENTEROCOLITIS

Clostridium difficile Colitis and Ischemic Colitis (Left) The green-yellow pseudomembrane in this colon is confluent. Only focal ulcerated mucosa is visible . The bowel wall is thickened and edematous . (Right) Pseudomembranous colitis is patchy, involving small clusters of crypts with epithelial cell necrosis and overlying necrotic debris of pseudomembrane with abrupt transition to normal glands . There is limited inflammation in the lamina propria .

(Left) The pseudomembranes on the mucosal surface of this colon are well demarcated and arise in the setting of ischemic colitis. The mucosa between the pseudomembranes is dusky , and histology showed ischemic colitis. (Right) At low power, ischemic colitis shows more involvement of the submucosa with edema and inflammation and necrosis in severe cases and is much more cellular than pseudomembranous colitis.

(Left) Necrotic debris erupts into bowel lumen from dilated crypts. The crypt in the center is lined by attenuated cells , and the crypt on the right demonstrates epithelial necrosis. (Right) The mucosa in ischemic colitis loses glandular architecture as opposed to pseudomembranous colitis where mucin-distended glands can still be identified even when the epithelium is necrotic, except in severe cases.

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Severe C. diff Colitis and Other Organ Changes (Left) This dilated and duskyappearing ascending colon is evolving toward toxic megacolon in a patient with known Clostridium difficile infection. Note the fibrinopurulent exudate on the serosal surface indicating transmural inflammation or perhaps even perforation. (Right) In severe disease (toxic megacolon), the mucosa becomes necrotic and inflammation extends more deeply though the wall , as in ischemic colitis.

(Left) This higher power view shows the acute inflammation expanding the submucosa in a case of toxic megacolon. (Right) This cell block preparation of ascitic fluid in a case of toxic megacolon contains innumerable polymorphonuclear leukocytes .

Disease Process Approach to Autopsy: Infection-Related Death

CLOSTRIDIUM DIFFICILE ENTEROCOLITIS

(Left) Cortical pallor and a congested medulla are apparent grossly in a kidney with acute tubular injury. (Right) Acute tubular injury has dilated tubules due to flattening of the epithelium, and cellular debris is noted in the tubular lumen .

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VIRAL HEPATITIS

This liver with green discoloration due to cholestasis shows areas of necrosis and capsular irregularity that is typically seen in fulminant viral hepatitis. (Courtesy of D. Rubin, MD.)

ETIOLOGY/PATHOGENESIS

CLINICAL ISSUES

Hepatotropic Viruses

Epidemiology

Hepatitis A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV)

Systemic Viruses Herpes virus group

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A trichrome stain highlights fibrous bands surrounding regenerative nodules in this liver with cirrhosis due to chronic hepatitis C infection.

Risk factors: Immunocompromised states, especially HIV, pregnancy, and neonatal period, rare in immunocompetent hosts Herpes simplex virus (HSV): Disseminated infection often fatal Cytomegalovirus (CMV): May cause infectious mononucleosis-like syndrome in immunocompetent Epstein-Barr virus (EBV): Infectious mononucleosis with liver involvement, lymphoproliferative disorders, and hemophagocytic syndrome (usually fatal) Varicella zoster virus (VZV) Human herpesvirus 6 (HHV-6): May cause hemophagocytic syndrome Viral hemorrhagic fevers (VHF) 4 families of RNA viruses: Filovirus (e.g., Marburg and Ebola), flavivirus (e.g., yellow fever, dengue), arenavirus (e.g., Argentine, Bolivian, Lassa, etc.), and bunyavirus (e.g., Rift Valley fever, hantavirus) Life cycles involve humans, primates, rodents, bats, mosquitos, and ticks; also nosocomial spread Severity and mortality vary, not all infected patients develop disease Hemorrhage due to abnormal vascular regulation/ damage capillary leakage effusions, edema, hemorrhage disseminated intravascular coagulation (DIC), hepatic/organ necrosis, shock Other viruses that rarely affect liver Adenovirus, enterovirus, parvovirus

Incidence

Hepatotropic viruses HAV: ~ 2,800 acute infections in USA (2011) HBV: ~ 18,000 acute infections in USA (2011), ~ 1 million chronic infections HCV: ~ 16,500 acute infections in USA (2011), ~ 3 million chronic infections HDV: Rare in US, ~ 5% of HBV carriers HEV: Clinical hepatitis rare in USA; seroprevalence may be higher Viral hemorrhagic fever Rare in USA, endemic viruses include dengue and Sin Nombre viruses

Presentation

Fever, jaundice, abdominal pain, nausea, vomiting, anorexia, fatigue, arthritis, pruritis, hematuria

Maculopapular, urticarial, purpural, or vesicular/ pustular rash, neurologic symptoms

Cough, dyspnea, hemoptysis (pneumonitis), chest pain and palpitations (myocarditis)

Headache, neck stiffness, photophobia, seizures (meningoencephalitis)

Petechial rash, epistaxis, melena, hematemesis, conjunctival bleeding, shock (VHF)

Important elements of chart review

Travel, food consumption, sexual history, history of injection drug use, blood transfusions, tattoos/ piercings, other blood/body fluid exposures, immunosuppression, sick contacts

Laboratory Tests

transaminases, bilirubin, ammonia, and fetoprotein, + viral hepatitis antibodies/RNA/DNA, + other viral serologies/RNA/DNA

Key Facts Etiology

Hepatotropic viruses: Hepatitis A, B, C, D, and E Herpes virus group: HSV, CMV, EBV, VZV, HHV-6 Viral hemorrhagic fevers: Yellow fever, dengue fever, Ebola, hantavirus, etc.

Clinical Issues

Important elements of chart review: Travel, food consumption, and sexual history, history of injection drug use, blood transfusions, tattoos/piercings, blood/ body fluid exposures, immunosuppression

Macroscopic Pathology

Acute hepatitis: Hepatomegaly, cholestasis, necrosis, regenerative nodules, hemorrhage

Chronic hepatitis: Hepatomegaly or atrophy,

Microscopic Pathology

Acute hepatitis (HAV, HBV HDV, HCV, HEV): Lobular inflammation, acidophil bodies, variable necrosis, swollen hepatocytes, lobular disarray, cholestasis, variable portal inflammation Chronic hepatitis (HBV HDV, HCV, rarely HEV): Portal inflammation, variable interface and lobular activity, fibrosis, cirrhosis, siderosis, dysplastic nodules, hepatocellular carcinoma

Reporting Considerations

Final report should include: Type of viral hepatitis, extent of hepatic disease, associated extrahepatic findings, whether the virus was the cause of death or a contributing factor

cirrhosis, masses

Postmortem blood testing for HBV and HCV antibodies and PCR has been shown to work Consider postmortem viral testing in cases of unknown liver injury blood urea nitrogen and creatinine, proteinuria, hematuria, hypocomplementemia, + serum cryoglobulins Thrombocytopenia, anemia, lymphocytosis, prolonged prothrombin and partial thromboplastin times C-reactive protein and erythrocyte sedimentation rate, pancytopenia, hemophagocytosis on blood smear

Prognosis

~ 25% chronic HBV and HCV infection will cirrhosis/chronic liver failure risk of hepatocellular carcinoma (HCC) Coinfection with HIV accelerates liver damage by HBV and HCV Mortality of acute viral hepatitis varies, higher in immunocompromised

MACROSCOPIC FEATURES External Examination/Autopsy Safety

Jaundice, scleral icterus, abdominal distension, pitting edema, anasarca, caput medusae, spider angiomas (liver failure/portal hypertension) Maculopapular, purpural, urticarial, pustular, vesicular rashes (viral exanthems) Pallor (shock), petechiae, gangrene, and mucocutaneous hemorrhage (DIC) Universal precautions mandatory in setting of necrotic or cirrhotic liver, always consider HIV coinfection

Internal Examination Ascites

Organ Examination Liver

Acute/fulminant hepatitis: Hepatomegaly, edematous capsule, green discoloration (cholestasis), necrosis atrophy with wrinkled capsule and regenerative nodules if extensive, hemorrhagic foci Chronic hepatitis: Hepatomegaly or atrophy, cirrhosis (usually macronodular), masses (HCC usually softer than surrounding nodules and vary in color necrosis) Other organs Necrosis/hemorrhage (DIC) Gastrointestinal tract: Ulcers, inflammation, gastric/ esophageal varices Lungs: Consolidation, edema Kidneys: Cortical pallor and medullary congestion (shock), atrophic with granular subcapsular surface (chronic glomerulonephritis) Spleen: Splenomegaly

Disease Process Approach to Autopsy: Infection-Related Death

VIRAL HEPATITIS

MICROSCOPIC PATHOLOGY Histologic Features Liver

Acute hepatitis (HAV, HBV HDV, HCV, HEV): Lobular inflammation, acidophil bodies, necrosis (spotty, confluent, bridging, submassive), swollen hepatocytes, lobular disarray parenchymal collapse, cholestasis, variable portal inflammation Specific findings in HAV: Periportal/interface inflammatory activity and necrosis, + plasma cells, perivenular cholestasis without inflammation/ necrosis Chronic hepatitis (HBV HDV, HCV, rarely HEV): Chronic hepatitis (portal inflammation) with variable interface and lobular inflammatory activity, variable fibrosis, cirrhosis, siderosis, HCC HBV: Ground-glass hepatocytes (cytoplasmic inclusions containing HBV surface antigen), "sanded" nuclei (pale pink inclusions containing HBV core antigen)

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VIRAL HEPATITIS

Summary of Hepatotropic Viruses Virus

Genome and Classification

Mode of Transmission

Type of Hepatitis

Hepatitis A

Single-stranded RNA, picornavirus

Fecal-oral

Acute, usually mild; may be Acute pancreatitis, protracted, relapsing, or fulminant thrombocytopenia, cryoglobulinemia (rare)

Hepatitis B

Incomplete double-stranded DNA, hepadnavirus

Parenteral, sexual, perinatal Acute with recovery reactivations, rarely fulminant, carriers without chronic hepatitis, chronic exacerbations

Glomerulonephritis, serum sickness-like syndrome, polyarteritis nodosa, GuillainBarr syndrome, cryoglobulinemia

Hepatitis C

Single-stranded RNA, hepacivirus

Parenteral; sexual and perinatal are less common

Glomerulonephritis, cryoglobulinemia, lichen planus, autoimmune diseases cytopenia, porphyria cutanea tarda, insulin resistance

Hepatitis D

Single-stranded RNA (defective), deltavirus

Parenteral and sexual, only May clear with clearance of N/A occurs with coinfection or hepatitis B (coinfection), chronic superinfection with hepatitis exacerbations and rarely B fulminant (superinfection)

Hepatitis E

Single-stranded RNA, hepevirus Fecal-oral

HDV: Same as HBV but usually more severe activity and necrosis HCV: Lymphoid aggregates germinal centers in portal tracts, acidophil bodies, steatosis, mild bile duct injury Rarely fibrosing cholestatic hepatitis in immunocompromised with HBV or HCV (periportal/perisinusoidal fibrosis, cholestasis, little/no inflammation) Nonhepatotropic viral hepatitis HSV: Geographic coagulative necrosis inflammation, purple glassy intranuclear inclusions with chromatin margination clear halo and multinucleation CMV: Intranuclear inclusions with clear halo, intracytoplasmic basophilic granules, microabscesses, infectious mononucleosislike syndrome (lymphocytes in sinusoids, no inclusions), neonatal giant cell hepatitis EBV: Diffuse sinusoidal lymphocytic infiltrates VZV: Variable necrosis, little inflammation, intranuclear inclusions HHV-6: Nonspecific lobular inflammation Viral hemorrhagic fevers Most appear similar with perivenular or mid-zonal necrosis without inflammation or cholestasis, steatosis, ballooned hepatocytes Other organs Esophageal/gastrointestinal ulcers viral inclusions Pneumonitis, myocarditis viral inclusions Glomerulonephritis, acute tubular injury/necrosis DIC: Widespread microthrombi hemorrhage and ischemic necrosis, schistocytes in peripheral blood

Chronic, rarely acute

Acute, fulminant in pregnancy, chronic in immunosuppressed

Extrahepatic Manifestations

Acute pancreatitis, aplastic anemia, neurologic diseases, acute thyroiditis, glomerulonephritis

ANCILLARY TESTS Immunohistochemistry

HBV surface and core antigens, HDV antigen, HSV, CMV, VZV, HHV-6, adenovirus, parvovirus, enterovirus

Some VHFs: Dengue ([+] in Kupffer cells), Lassa, Ebola

In Situ Hybridization EBER for EBV

Special Stains

Trichrome to evaluate fibrosis/staging Iron stain for siderosis Reticulin stain to evaluate sinusoidal architecture and presence of parenchymal collapse

REPORTING CRITERIA Final Report Should Include

Type of viral hepatitis, extent of hepatic disease, associated extrahepatic findings, whether virus was the cause of death or a contributing factor

SELECTED REFERENCES 1. 2. 3.

Dalton HR et al: Hepatitis E. Curr Opin Infect Dis. 26(5):471-8, 2013 Paessler S et al: Pathogenesis of the viral hemorrhagic fevers. Annu Rev Pathol. 8:411-40, 2013 Eriksen MB et al: Postmortem detection of hepatitis B, C, and human immunodeficiency virus genomes in blood samples from drug-related deaths in Denmark*. J Forensic Sci. 54(5):1085-8, 2009 Amarapurkar DN et al: Extrahepatic manifestations of viral hepatitis. Ann Hepatol. 1(4):192-5, 2002

Microscopic Findings in Viral Hepatitis (Left) Ground-glass hepatocytes as seen in hepatitis B infection are characterized by homogeneous pink intracytoplasmic "glassy" inclusions , often surrounded by a clear halo. These inclusions contain hepatitis B surface antigen. (Right) Immunohistochemical stain for hepatitis B surface antigen (HBsAg) is positive in the cytoplasmic inclusions of the groundglass hepatocytes.

(Left) Lymphoid aggregates in portal tracts are characteristic of chronic hepatitis C infection. Occasionally, the aggregates contain reactive germinal centers . (Right) Herpes simplex virus (HSV) hepatitis is associated with irregular areas of necrosis . Scattered viable hepatocytes show glassy intranuclear inclusions with chromatin margination and multinucleation , which are characteristic of herpes virus infection.

Disease Process Approach to Autopsy: Infection-Related Death

VIRAL HEPATITIS

(Left) This liver shows diffuse sinusoidal lymphocytic infiltrates without significant necrosis that is characteristic of EpsteinBarr virus (EBV) hepatitis. Patchy steatosis may also be present. (Right) In situ hybridization for EBV (EBER) is positive in the nuclei of numerous lymphocytes that infiltrate the sinusoidal spaces in this case of EBV hepatitis.

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UROSEPSIS

This bisected kidney shows hydronephrosis with dilated calyces and a kidney stone . Nephrolithiasis is the most common cause of urinary obstruction in young adult patients.

TERMINOLOGY

CLINICAL ISSUES

Definitions

Clinical Presentations

Sepsis: Systemic inflammatory response syndrome (SIRS) caused by infection Urosepsis: Sepsis as a result of a complicated urinary tract infection ~ 25% of sepsis Complicated cystitis/pyelonephritis: Infection of bladder/upper urinary tract and kidney associated with condition that increases possibility of treatment failure Diabetes, pregnancy, urinary obstruction, catheters, instrumentation, stones, anatomic abnormality

ETIOLOGY/PATHOGENESIS Infectious Agents

Enteric gram-negative rods, e.g., Escherichia coli, Klebsiella, Enterobacter, Proteus

Pseudomonas Enterococci Fungi, especially Candida albicans and Candida glabrata

Ascending Infections

Most common Fecal contamination of urethra urethritis cystitis pyelonephritis

Enterococci, especially in hospitalized/ institutionalized patients with urinary catheters

Blood-Borne Infections

Much less common Staphylococcus aureus: From skin/soft tissue infection or

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The heart in this patient with urosepsis and disseminated intravascular coagulation (DIC) shows epicardial petechial hemorrhages as well as pleural and pericardial effusions.

aortic bacterial endocarditis Pyelonephritis, often with abscess formation Mycobacterium tuberculosis (MTB) Complication of disseminated pulmonary TB Clinical picture UTI with negative bacterial cultures

Cystitis: Dysuria, urinary frequency, urinary urgency Pyelonephritis Same as cystitis, plus fever, costovertebral angle tenderness Urosepsis Complicated urinary tract infection, SIRS, multiorgan failure, disseminated intravascular coagulation (DIC)

Risk Factors

Urinary obstruction

Congenital Strictures: Ureteral or urethral Polycystic kidney disease Acquired Calculi: Most common cause of obstruction in young adults Prostatic hyperplasia: Most common cause of obstruction in older men Tumors Pregnancy: Some degree of hydroureter/ hydronephrosis is normal in pregnancy Complication of radiation therapy Instrumentation Urethral catheter, ureteral stent, nephrostomy Impaired voiding Neurogenic bladder Cystocele/prolapse Vesicoureteral reflux Metabolic disorders Diabetes (especially atypical pathogens) Nephrocalcinosis

Key Facts Terminology

Urosepsis is defined as SIRS in setting of complicated urinary tract infection

Accounts for 25% of all cases of sepsis Certain groups are at increased risk of urosepsis

Patients with abnormal urinary tract anatomy Patients with urinary tract catheters/hardware or history of urinary tract procedure Patients with certain underlying conditions: Diabetes, sickle cell, neurogenic bladder Usually result of ascending infection Most often gram-negative enteric bacteria Enterococci: In institutional settings in catheterized patients Secondary involvement of urinary tract by bloodstream infection is less common

Typically Staphylococcus aureus Urinary tract findings Obstructive lesions: Extrinsic tumors, prostatic enlargement, bladder distension and trabeculation, hydroureter, hydronephrosis Inflammatory urinary tract changes: Cystitis, pyelonephritis, renal abscess Findings associated with sepsis Changes of disseminated intravascular coagulation: Petechiae, ecchymoses, microthrombi Anasarca, effusions Diffuse alveolar damage Changes of septic organ injury and failure

Disseminated intravascular coagulation Widely scattered microthrombi Evidence of ischemic organ injury Diffuse alveolar damage

MACROSCOPIC FEATURES External Examination in Sepsis Edema (anasarca)

Capillary leak (SIRS) Aggressive intravenous fluid therapy Petechial hemorrhages (DIC)

Internal Examination Urethral obstruction

Bladder distension and trabeculation Prostate enlargement Ureteral obstruction Obstructing lesion (e.g., tumor) Hydroureter: Dilated and sometimes tortuous Hydronephrosis: Thinned parenchyma and compressed papillae are signs of chronicity Nephrolithiasis

Organ Examination

Urinary Tract: Possible findings

Acute pyelonephritis Cortical abscesses: Especially with nephrolithiasis or reflux Renal papillae with yellow streaks Renal papillary necrosis Diabetics and patients with sickle cell Cystitis Hyperemic, boggy mucosa with cloudy urine

Disease Process Approach to Autopsy: Infection-Related Death

UROSEPSIS

ANCILLARY TESTS Histochemistry

Gram stain of fresh tissue

Less reliable in postmortem tissue Nonviable gram positive organisms may appear gram negative Special stains for bacteria in formalin fixed, paraffinembedded tissue Brown-Brenn or Brown-Hopp stain: Gram positive organisms blue, gram negative organisms red, nuclei red, background yellow Alternatives: Taylor stain, Lisa stain Special stains for fungi in formalin-fixed, paraffinembedded tissue GMS, PAS

Bacterial Cultures

Not necessary if positive premortem cultures Low yield in patients on broad spectrum antibiotics Blood and splenic cultures to prove systemic infection Urine cultures only diagnostic if they match blood or splenic cultures

Molecular Testing

MICROSCOPIC PATHOLOGY

Molecular microbiology in formalin-fixed, paraffinembedded tissue Probes for species specific DNA sequences for prokaryotic ribosomes

Histologic Features

Evidence of local inflammation/infection

Acute pyelonephritis Abscesses with destruction of tubules Acute inflammation with neutrophil casts Glomeruli usually spared Cystitis Evidence of systemic inflammatory response/ coagulopathy

SELECTED REFERENCES 1. 2.

Kalra OP et al: Approach to a patient with urosepsis. J Glob Infect Dis. 1(1):57-63, 2009 Annane D et al: Septic shock. Lancet. 365(9453):63-78, 2005

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UROSEPSIS

Gross and Histologic Features (Left) These petechial skin hemorrhages in a patient with urosepsis are one manifestation of DIC. DIC is characterized by diffusely scattered microthrombi and diffuse petechial hemorrhages in the skin as well as mucosal and serosal surfaces. (Right) These cross sections of ventricles from a patient dying from sepsis and multiple organ dysfunction syndrome show a markedly dilated right ventricle . The patient also showed hepatic necrosis and anasarca.

(Left) Gross image shows an abrupt transition from hydroureter on the left to normal diameter ureter on the right . The ureter was compressed by a tumor. Abnormal anatomy, reflux, obstruction, and stones increase the risk of urinary tract infection. (Right) The congested mucosa and tanyellow exudate indicate acute cystitis. The trabeculation suggests chronic urethral obstruction. Prostatic hyperplasia with urethral obstruction is a common risk factor for urosepsis in older men.

(Left) Scattered tan-yellow cortical abscesses with hyperemic, red borders can be seen in this case of acute pyelonephritis. Renal abscesses are more common in patients with nephrolithiasis or vesicoureteral reflux. (Right) Necrotizing acute inflammation can be seen in this section taken from a renal abscess. Although most commonly the result of ascending enteric infections, this can also be seen with hematogenously spread Staphylococcus aureus.

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Histologic and Microbiologic Features (Left) Pyelonephritis is characterized by interstitial acute inflammation with sparing of the glomeruli. Neutrophils may fill the tubules and result in neutrophil casts seen on urinalysis. (Right) This section shows the nodular glomerulosclerosis and sclerotic glomeruli characteristically seen in the kidneys of diabetic patients. Diabetics are at increased risk for complicated urinary tract infections and urosepsis and may have infections with unusual organisms.

(Left) The thick gramnegative rods seen in this Gram stain are typical of organisms like E. coli and other enterics, which cause urinary tract infections. Other common causative gram-negative rods include Proteus, Klebsiella, and Enterobacter. (Right) This blood agar/MacConkey agar biplate shows the characteristic appearance of Escherichia coli, the most common cause of urosepsis.The majority of cases of urosepsis are caused by ascending infections with enteric organisms.

(Left) Enterococcus, a Gram-positive coccus that grows in chains, is a particularly important cause of hospital-acquired urinary tract infections. Risk factors include urinary catheterization, older age, severe underlying illness, and prior antibiotic therapy. (Right) Enterococci grow only on the blood agar portion of a biplate and not on MacConkey agar, which selects for gramnegatives. A significant fraction of hospital-acquired enterococci are multiply drug resistant.

Disease Process Approach to Autopsy: Infection-Related Death

UROSEPSIS

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SECTION 3

Neoplasia-Associated Death

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% 5

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Disease Process Approach to Autopsy: Neoplasia-Associated Death

NEOPLASIA-ASSOCIATED DEATH

This patient had an occult malignancy at autopsy that had metastasized to the pulmonary arteries and caused thrombosis with organization . Tumor cells can be seen in the organizing thrombus .

TERMINOLOGY Direct Tumor Effects Mass effect

Respiratory: Bronchial obstruction and postobstructive pneumonia Gastrointestinal tract: Obstruction malnutrition, intestinal ischemia, etc. CNS: May cause brain swelling and herniation SVC syndrome: Obstruction to blood flow in superior vena cava (most commonly due to malignancy [usually lung])

Paraneoplastic Effects

Paraneoplastic syndromes (PNS) are systemic effects of

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tumors not due to metastatic disease 2 main mechanisms for PNS: Secreted tumor product and immunologic cross reactivity between tumor and normal tissues May not cause death but contributes to death; is clue to underlying malignancy Neurological, endocrine, dermatologic, hematologic manifestations most common Neurological: Limbic encephalitis, paraneoplastic cerebellar degeneration; Lambert-Eaton syndrome and myasthenia gravis; autonomic neuropathy and subacute sensory neuropathy Dermatologic: Dermatomyositis, acanthosis nigricans, paraneoplastic pemphigus Endocrine: Syndrome of inappropriate antidiuretic hormone secretion (SIADH), Cushing syndrome, hypoglycemia, carcinoid syndrome (flushing, diarrhea, and bronchospasm) Hematologic: Eosinophilia, granulocytosis, thrombocytosis, pure red cell aplasia (thymoma, leukemias/lymphomas, and myelodysplastic syndromes) Amyloidosis (AL) and myeloma cast nephropathy: Secretion of light chains by myeloma may cause

An elastic stain demonstrates the disrupted elastic lamina of the artery in this case with organizing tumor thromboemboli.

extracellular deposits as amyloid fibrils or light chain cast nephropathy

Morbidity and Mortality Associated With Tumor Therapy

Tumor lysis syndrome: Metabolic derangement seen with lysis of large numbers of tumor cells usually seen 48-72 hours after initial treatment of non-Hodgkin lymphoma and leukemias Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia Usually acute renal failure due to uric acid nephropathy and nephrocalcinosis Graft-vs.-host disease (GVHD): Immune-mediated disease following allogeneic bone marrow or (rarely) solid organ transplantation In setting of neoplasia, GVHD usually follows allogeneic stem cell or bone marrow transplantation 3 criteria for GVHD to occur: Immune competent graft, disparate (nonidentical) recipient, immunocompromised recipient Systemic disease most often affecting skin, liver, and gastrointestinal tract Infection Bacterial and fungal infections are major complication of tumor therapy with attendant immunosuppression Radiation injury Effects of ionizing radiation include mucosal necrosis (early) to fibrosis (late); diffuse alveolar damage and fibrosis of lungs; skin erythema (early) to depigmentation and fibrosis (late); lymph node fibrosis

Thrombophilia

Very common, often lethal complication of malignancy, multifactorial in etiology: Host response to tumor, tumor effects, and therapy

Key Facts Terminology

Paraneoplastic syndromes (PNS) are systemic effects of tumors not due to metastatic disease 2 main mechanisms for PNS: Secreted tumor product and immunologic cross-reactivity between tumor and normal tissues Tumor lysis syndrome: Metabolic derangement usually seen 48-72 hours after initial treatment due to massive lysis lymphoma/leukemia cells Graft-vs.-host disease (GVHD): Immune-mediated disease following allogeneic stem cell transplantation 3 criteria for GVHD to occur: Immune competent graft, disparate (nonidentical) recipient, immunocompromised recipient Manifestations of thrombophilia in malignancy

Host response: Acute phase reactants, inflammation, necrosis, hemodynamic disturbances Tumor: Secretion of factors by tumor cells that promote coagulation, angiogenesis, fibrinolysis and inflammation; direct tumor interaction with endothelial cells, platelets, and leukocytes stimulating their procoagulant properties Tumor therapy: Direct injury to endothelial cells (radiation therapy, bleomycin, anti-VEGF, thalidomide, gemcitabine), hormonal therapy (tamoxifen) Venous thromboembolism (15% of cancer patients have thrombotic complication) Migratory thrombophlebitis: Recurrent venous thrombosis that moves (migratory) and affects superficial veins at uncommon sites (e.g., arms and chest wall) Often associated with mucinous adenocarcinoma Commonly referred to as Trousseau syndrome or Trousseau sign of malignancy Nonbacterial thrombotic endocarditis (NBTE): Sterile thrombi usually along the closing edge of valves; can embolize and rarely may cause death Thrombotic microangiopathy (TMA): Usually related to cancer therapy, including bone marrow transplantation

MACROSCOPIC FEATURES External Examination

Signs of potential underlying malignancy

Dermatologic: Acanthosis nigricans Thickened, hyperpigmented skin, axilla, and neck Dermatomyositis/polymyositis Purple (heliotrope) rash on upper eyelids, erythematous rash on upper body (face, neck, back, chest, and shoulders) Paraneoplastic pemphigus Blistering disease with superficial vesicles and bullae that rupture easily leaving erythematous base, mucosal involvement common

Trousseaus syndrome: Often associated with pancreatic adenocarcinoma and other mucinous adenocarcinomas Venous thromboembolism Migratory thrombophlebitis: Recurrent venous thrombosis that changes location (migratory) often affecting superficial veins Nonbacterial thrombotic endocarditis (NBTE): Sterile thrombi usually along closing edge of valves; can embolize Thrombotic microangiopathy (TMA): Usually related to cancer therapy

SVC syndrome: Facial plethora and congestion, upper extremity swelling Signs of therapy Port-a-cath: Permanent intravenous lines with subcutaneous port in subcutaneous tissue of chest (usually left sided) GVHD skin changes Acute GVHD: (within 100 days of transplant) erythematous macules characteristically on palms and soles Chronic GVHD: (after 100 days) lichenoid plaques or scleroderma- like changes

Disease Process Approach to Autopsy: Neoplasia-Associated Death

NEOPLASIA-ASSOCIATED DEATH

Organ Examination Primary tumor

Size and extent, regional lymph node, and organ metastases or document no residual tumor Document prior therapy (resections, radioactive seeds) Thrombophilic complications Pulmonary thromboembolism (PTE) is most lethal thrombotic complication of neoplasia and associated therapy Thrombotic microangiopathy may not have gross findings but may show small petechial hemorrhages in renal cortex Infectious complications Respiratory Pneumonia (viral, bacterial, and fungal) characterized by areas of consolidation: Fungal pneumonia often with targetoid areas of central necrosis with surrounding hemorrhage due to vasculotropic nature of many fungal infections Diffuse congestion and consolidation: Diffuse alveolar damage (infection/shock) Gastrointestinal Ulcerative infection from virus (punched-out ulcers: HSV, shallow ulcers: CMV), candidal infection (pseudomembranes), neutropenic enterocolitis (segmental ulceration, inflammation of terminal ileum, cecum, and ascending colon [a.k.a. typhlitis])

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Disease Process Approach to Autopsy: Neoplasia-Associated Death

NEOPLASIA-ASSOCIATED DEATH Direct tumor complications

Mass effects CNS: Brain swelling with enlargement of gyri and effacement of sulci; tonsillar herniation of cerebellar tonsils through foramen magnum is lethal SVC syndrome: Tumor (usually lung primary) surrounds superior vena cava thrombosis Hemorrhage and extensive necrosis Extensive hemorrhage into tumor may extend into body cavity (e.g., peritoneal hemorrhage with hepatocellular tumors) shock Extensive necrosis of large amounts of tumor such as leukemias and lymphomas may be associated with tumor lysis syndrome Graft-vs.-host disease Ulcerations and edema in gastrointestinal tract and cholestatic-appearing liver Paraneoplastic syndromes Carcinoid syndrome Carcinoid tumor either metastatic from intestine to liver/lung or primary ovarian carcinoid (vasoactive amines that carcinoid syndrome are inactivated by liver and lung) Cardiovascular: Plaques form along endocardial surface of right heart and tricuspid and pulmonic valves, pulmonary artery

MICROSCOPIC PATHOLOGY Histologic Features

Primary tumor, determine type, extent (stage), and

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differentiation (grade) Thrombotic complications PTE: Thromboembolus should have layered fibrin and red blood cells; presence of tumor cells indicates tumor thrombus NBTE: Small (1-5 mm) fibrin thrombi loosely attached to closing edge of valve (usually left heart), without associated inflammatory response Strong association with mucinous adenocarcinoma Thrombotic microangiopathy: Kidney most frequently affected Diffuse endothelial swelling, arteriolar and capillary thrombi, thickened glomerular capillary walls (subendothelial debris and fibrin) Tumor lysis syndrome Best seen in kidney: Acute tubular injury with urate crystal deposition and calcinosis (calcification of tubular cells, tubular basement membrane, and calcified tubular casts) PNS: Neurologic Limbic encephalitis: Perivascular inflammation, some neuronal loss and microglial nodules in anterior and medial temporal lobe Paraneoplastic cerebellar degeneration: Destruction of Purkinje cells, gliosis, mild inflammation PNS: Dermatologic

AN: Epidermis and dermal papillae undulate (peaks and valleys), variable hyperplasia, basal cell hyperpigmentation and hyperkeratosis Paraneoplastic pemphigus: Suprabasal acantholytic blister, immunofluorescence with anti-IgG shows staining of plasma membrane of epidermal cells PNS: Other Amyloidosis: Extracellular deposition of hyaline material that stains with congo red and shows apple-green birefringence; immunofluorescence will demonstrate isolated light chain, usually lambda Carcinoid syndrome: Plaques within cardiovascular system composed of smooth muscle cells in mucopolysaccharide-rich matrix without changes to underlying endocardial tissue Graft-vs.-host disease Epidermal and mucosal epithelial apoptosis with associated, usually mild lymphocytic infiltrate Liver: Bile duct inflammation (early), bile duct epithelial degenerative change (late), bile duct loss (late), cholestasis Radiation injury Vascular injury: Endothelial swelling and occasionally necrosis (early); intimal fibrosis (late) Interstitial fibrosis often containing atypical cells with prominent nucleoli and giant cell formation

REPORTING CRITERIA Tumor Classification, Staging, and Grading in Final Report Most commonly staging system is TNM: T = tumor, N = lymph nodes, M = metastatic disease

Prefix "a" indicates diagnosis at autopsy (e.g., aT3N1M1)

Quality Assurance

Compare tumor type, grading, and staging to prior pathology reports; address discrepancies

SELECTED REFERENCES 1. 2.

Deng A et al: Venous thromboembolism in cancer patients. Hosp Pract (1995). 42(5):24-33, 2014 Phan M et al: Primary venous thromboembolism prophylaxis in patients with solid tumors: a meta-analysis. J Thromb Thrombolysis. 38(2):241-9, 2014 Connolly GC et al: Cancer-associated thrombosis. Hematology Am Soc Hematol Educ Program. 2013:684-91, 2013 Jones LM et al: Cardiovascular disease among breast cancer survivors: the call for a clinical vascular health toolbox. Breast Cancer Res Treat. 142(3):645-53, 2013

Infectious & Paraneoplastic Complications of Malignancy (Left) This lung demonstrates fungal pneumonia with multiple areas of consolidation and abscess formation with necrosis . (From DP: Transplant.) (Right) A GMS stain reveals the presence of septate hyphae that branch at acute angles consistent with aspergillosis. (From DP: Transplant.)

(Left) The ulcers caused by cytomegalovirus are shallow as opposed to the punched-out ulcers of herpes simplex virus. (From DP: Endoscopic.) (Right) Cytomegalovirus inclusion in an endothelial cell is shown. There is an intranuclear "owl’s-eye" basophilic inclusion surrounded by an area of clearing and smaller intracytoplasmic basophilic inclusions . (From DP: Kidney.)

Disease Process Approach to Autopsy: Neoplasia-Associated Death

NEOPLASIA-ASSOCIATED DEATH

(Left) In paraneoplastic cerebellar degeneration, perivascular inflammation and Purkinje cell loss are noted. (From DP: Neuro.) (Right) This von Kossa stain for calcium phosphate demonstrates staining of the tubular basement membranes and interstitium in a case of nephrocalcinosis. (From DP: Kidney.)

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Disease Process Approach to Autopsy: Neoplasia-Associated Death

NEOPLASIA-ASSOCIATED DEATH

Malignancy, General Features (Left) This parietal pleural surface on the right chest (thoracic vertebrae , ) is red and granular ribs due to recent instillation of tetracycline for pleurodesis for malignant pleural effusion. (Right) Cytology of the pleural fluid revealed clusters of malignant cells (high nuclear to cytoplasmic ratio, nuclear pleomorphism) with intracytoplasmic mucin vacuoles consistent with lung adenocarcinoma. Cytology of postmortem material-like effusions can yield diagnostic information. (From DP: Cytopathology.)

(Left) Tumor mass effects include obstruction. This colon cancer has a "napkin ring" patten causing colonic obstruction. This tumor would be measured and the transmural invasion documented to stage it according to TNM staging system. (From DP: Endoscopic.) (Right) Limited metastatic disease to the liver in a colon cancer, as shown here , would be recorded as an M1a (metastasis confined to 1 organ or site).

(Left) Marked cachexia with severe loss of adipose tissue and muscle mass as noted here by prominent bony protrusions and marked muscular atrophy is common in malignancy and felt to be due to effects of TNF on metabolism. (Right) This scar is associated with a port-a-cath reservoir on the anterior chest wall of a patient with malignancy. These devices must be checked for placement and any associated infection at autopsy of patients with malignancy.

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Therapeutic Complications (Left) This resected atrioventricular valve shows the characteristic plaques of carcinoid valve disease. They lay over the valvular leaflet as well as chordae tendinea . (From DP: Cardiovascular.) (Right) An elastic stain reveals the carcinoid plaque to be devoid of elastic tissue , which is limited to the valve tissue . There is no injury to the underlying valve tissue. The plaque is comprised of smooth muscle cells in a matrix rich in acid mucopolysaccharides. (From DP: Cardiovascular.)

(Left) Histologically, there were scattered apoptotic squamous cells in the epithelium . (From DP: Endoscopic.) (Right) With more severe graft-vs.-host disease, there is more extensive epithelial apoptosis that can progress to frank necrosis and ulceration. Lymphocytic inflammation is present . (From DP: Endoscopic.)

Disease Process Approach to Autopsy: Neoplasia-Associated Death

NEOPLASIA-ASSOCIATED DEATH

(Left) This small bowel was resected due to obstruction following radiation therapy for gynecologic malignancy. The bowel wall is markedly thickened due to fibrosis. (From DP: Endoscopic.) (Right) Radiation therapy leads to marked intimal fibrosis of the arteries and may lead to complete obstruction of the lumen . (From DP: Endoscopic.)

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Disease Process Approach to Autopsy: Neoplasia-Associated Death

DEATH DUE TO PARANEOPLASTIC EFFECT

Marantic endocarditis is also known as nonbacterial thrombotic endocarditis. Note the small valve vegetations , a result of a tumor-associated hypercoagulable state.

TERMINOLOGY Definitions

Paraneoplastic syndromes

Remote effects (signs and symptoms) produced by tumor Not related to mass effect, invasion, obstruction, or metastasis Definition excludes infections, nutritional effects, and complications of therapy Often precede malignant diagnosis

ETIOLOGY/PATHOGENESIS Commonly Associated Tumors Lung

Particularly small cell lung carcinoma (SCLC)

Hematolymphoid Breast Ovary Kidney

Mechanisms

Tumor-produced humoral factors: Hormones, cytokines, enzymes, precursors, etc. e.g., neuroendocrine tumors of pancreas Altered immune response: Cross-reactive antitumor antibodies e.g., onconeural antibodies

CLINICAL ISSUES Epidemiology Incidence

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Overall incidence estimated at 1-20% of malignancies Likely represents an underestimate Incidence for some specific tumor types

Hypertrophic osteoarthropathy is characterized in part by by digital clubbing. Widening of the distal phalanx is due to collagen deposition and capillary proliferation.

5% of cases of small cell lung cancer 10% of cases of lymphoma, myeloma 10-40% of cases of renal cell carcinoma Age Later in life (median: 6th decade) Gender Women with SCLC have increased risk of paraneoplastic encephalomyelitis Gender distribution in other clinical scenarios uncertain Hormone-producing tumors especially may be part of an inherited syndrome Multiple endocrine neoplasia type 1 von Hippel-Lindau disease Neurofibromatosis type 1 Tuberous sclerosis

Presentation General

Most of these syndromes may also be seen in absence of a tumor Clinicopathologic correlation is essential Paraneoplastic syndrome may be 1st sign of malignancy Some paraneoplastic syndromes will resolve with successful tumor treatment Typically true of endocrine paraneoplastic syndromes Other paraneoplastic syndromes may persist despite tumor treatment Especially true of immune-mediated and neurologic paraneoplastic syndromes Cutaneous Dermatomyositis Heliotrope facial rash Periorbital edema Erythematous papules on extensor surfaces of joints (Gottron sign) Progressive proximal muscle weakness

Key Facts Terminology

Paraneoplastic syndromes are remote effects of tumors, not related to invasion, metastasis, or obstruction Typically produced by 1 of 2 mechanisms Tumor-elaborated substance (hormones, cytokines, enzymes, etc.) Cross-reacting antitumor antibodies (especially in neuromuscular paraneoplastic syndromes) Clinical syndrome of a paraneoplastic syndrome may present before or after diagnosis of underlying tumor Demonstration of paraneoplastic syndromes may be challenging Occur in an estimated 1-20% of cases of malignant tumors Tumors may be occult and small

Erythema nodosum Melanosis cutis Gray discoloration of skin distant from primary tumor May be diffuse or localized No associated tumor cells Acanthosis nigricans Strong association with malignancy Velvety, gray-black epidermal hyperplasia Most typically in skin folds (axillary, inguinal) Strong association with malignancy Syndrome of Leser-Trelt Sudden eruption of numerous seborrheic keratoses Existing seborrheic keratoses may increase in size May be associated with acanthosis nigricans New nonpigmented lanugo hair Acquired ichthyosis Necrolytic migratory erythema Often associated with glucagon-producing tumors (e.g., pancreatic neuroendocrine tumor) Sweet syndrome Scleroderma Neuromuscular Lambert-Eaton myasthenia Proximal muscle weakness Often SCLC Myasthenia gravis Antibodies directed toward neuromuscular acetylcholine receptors Muscle weakness Associated with thymoma (15% of cases) Subacute sensory neuronopathy Most often with SCLC Opsoclonus-myoclonus: Disordered ocular motility and multifocal myoclonus Pediatric patients: Associated with neuroblastoma Adult patients: Especially breast and gynecologic cancer Cerebellar degeneration: Diplopia, vertigo, gait disturbances, nystagmus, dysarthria Encephalomyelitis

Clinical presentations are often nonspecific and may be seen unassociated with tumors Clinicopathologic correlation is essential Review clinical records, including laboratory and imaging results, carefully Perform a diligent external examination Perform a thorough gross and histologic examination Sample thoroughly for histology Almost any tumor may be associated, but most common are lung (especially small cell carcinoma), hematolymphoid, kidney, breast, and ovary

Limbic encephalitis: Rapid-onset mental status changes and seizures, antibody mediated Gastrointestinal Zollinger-Ellison syndrome Result of gastrin-producing tumors (e.g., pancreatic neuroendocrine tumors) Gastroduodenal ulcers as well as ulcers in atypical locations Refractory to standard therapy Orthopedic Hypertrophic osteoarthropathy Digital clubbing, arthralgias, and ossifying periostitis Tumor-related osteomalacia Bone pain, hypophosphatemia, phosphaturia, low vitamin D May be caused by tumor-produced fibroblast growth factor 23 (FGF23) Mesenchymal hyperphosphaturic tumors, lung cancer, multiple myeloma, prostate cancer; often small tumors Metabolic/endocrine Hypercalcemia Tumor-associated parathyroid hormone production Squamous cell carcinoma of lung Renal cell carcinoma (15-20%) Syndrome of inappropriate antidiuretic hormone production (SIADH) Tumor-produced ADH, often by SCLC (75%) Rarely non-small cell lung cancer, head and neck cancer, esthesioneuroblastoma Euvolemic hyponatremia; may be associated with seizures and mental status changes Hypoglycemia Insulin-producing tumors (e.g., pancreatic neuroendocrine tumors) Cushing syndrome Result of tumor-produced adrenocorticotrophic hormone (ACTH) SCLC most common

Disease Process Approach to Autopsy: Neoplasia-Associated Death

DEATH DUE TO PARANEOPLASTIC EFFECT

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Disease Process Approach to Autopsy: Neoplasia-Associated Death

DEATH DUE TO PARANEOPLASTIC EFFECT Rarely, thyroid, adrenal, thymic, or pancreatic tumors Carcinoid syndrome Episodic cutaneous flushing, watery diarrhea May produce endocardial and valvular changes Neuroendocrine tumor production of vasoactive peptides Typically midgut neuroendocrine tumors with liver metastasis 10% of cases associated with bronchial neuroendocrine tumors 1% pancreatic neuroendocrine tumors Hematologic Migratory thrombophlebitis (Trousseau syndrome) Classically seen with gastrointestinal adenocarcinomas, but may be seen with many other types Marantic endocarditis Result of tumor-associated hypercoagulable state May produce emboli and ischemic symptoms Most commonly with adenocarcinoma of lung or pancreas Erythrocytosis Tumor-produced erythropoietin, often by renal cell carcinomas (1-8%) Less commonly: Hepatocellular carcinoma, Wilms tumor, cerebellar hemangioblastoma, sarcomas Eosinophilia Hodgkin disease and mycosis fungoides

Laboratory Tests

Tumor-secreted substances

Can be used clinically as tumor markers Carcinoid syndrome Elevated 24-hour urine 5-HIAA Tumor-associated antibodies Antineuronal antibodies Anti-Hu: Tumor-associated cerebellar degeneration and encephalomyelitis Anti-Yo: Tumor-associated cerebellar degeneration, especially with ovarian or breast tumors Anti-acetylcholine receptor antibody: Myasthenia gravis Anti-voltage-gated calcium channel antibodies Lambert-Eaton myasthenic syndrome Electrolytes SIADH Hyponatremia, hypo-osmolality, urine sodium > 40 mEq/L Tumor-related osteomalacia Hypophosphatemia, hyperphosphaturia, low vitamin D

Muscle wasting Digital clubbing: Hypertrophic osteoarthropathy Cushing syndrome Truncal obesity, dorsocervical fat ("buffalo hump"), cutaneous striae, hirsutism, bruising Skin Document appearance and distribution of lesions Consider biopsy, but not of hands or face Consequences of tumor-related pruritus Linear excoriations Related skin infections

Internal Examination

Thorough examination and sampling essential Underlying tumor may be inconspicuous Examine breasts Run entire gastrointestinal tract Thorough sectioning of pancreas

Organ Examination

Carcinoid syndrome-related heart disease

Fibrous endocardial fibrous plaques on valve leaflets and cardiac chambers Right heart more often than left heart

MICROSCOPIC PATHOLOGY Histologic Features

Paraneoplastic cerebellar ataxia

Loss of Purkinje cells Lymphocytic inflammation Tumor-related osteomalacia Tumors often small and inconspicuous Spindle and giant cell pattern Marantic endocarditis Valve vegetations composed of fibrin and platelets Typically lack inflammatory cells and microorganisms

SELECTED REFERENCES 1.

3. 4.

5. 6.

MACROSCOPIC FEATURES External Examination General

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Tumor-associated cachexia Body mass index Estimation of adipose tissue: Thickness of abdominal pannus

Ito T et al: Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 26(6):737-53, 2012 Pelosof LC et al: Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 85(9):838-54, 2010 Dalmau J et al: Paraneoplastic syndromes of the CNS. Lancet Neurol. 7(4):327-40, 2008 Rees JH: Paraneoplastic syndromes: when to suspect, how to confirm, and how to manage. J Neurol Neurosurg Psychiatry. 75 Suppl 2:ii43-50, 2004 Boyce S et al: Paraneoplastic dermatoses. Dermatol Clin. 20(3):523-32, 2002 Palapattu GS et al: Paraneoplastic syndromes in urologic malignancy: the many faces of renal cell carcinoma. Rev Urol. 4(4):163-70, 2002

Gross and Histologic Features (Left) Lester-Trelt sign refers to the sudden appearance of multiple new seborrheic keratoses and the rapid increase in size of existing seborrheic keratoses. (Right) This patient with scleroderma has characteristic digital ulcers . Scleroderma and systemic lupus are associated with increased risk of malignancy (this patient had lung carcinoma). Some scleroderma patients also have tumor-directed antibodies that cross-react with RNA polymerase.

(Left) Melanosis cutis (diffuse or localized) is the deposition of melanin pigment in skin not directly affected by melanoma and is usually seen in advanced cases. (Right) Neuroendocrine tumors (NET), especially small cell lung cancers, are particularly likely to be associated with paraneoplastic syndromes. In addition to producing biologically active peptides, they may be associated with antineuronal antibodies. The cut surface of a NET of the lung is seen.

(Left) Thymoma is associated with myasthenia gravis in 15% of cases. This section of thymoma stained with CK5/6 shows the characteristic nodularity and biphasic nature of the tumor (the background cells are T cells). (Right) This clear cell renal cell carcinoma (RCC) shows characteristic chicken-wire vascularity . RCC is associated with a paraneoplastic syndrome (such as polycythemia or hypercalcemia) in 10-40% of cases. Some RCCs produce renin and can result in hypertension.

Disease Process Approach to Autopsy: Neoplasia-Associated Death

DEATH DUE TO PARANEOPLASTIC EFFECT

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SECTION 4

Other Common Hospital Death

Chronic Obstructive Pulmonary Disease

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Ventilator Dependent Respiratory Failure

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Chronic Liver Failure

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Chronic Renal Failure

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Dementia and Neurodegenerative Disease

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Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

These emphysematous lungs, shown in situ, are hyperinflated and obscure the heart. Note the anthracotic pigment.

TERMINOLOGY

ETIOLOGY/PATHOGENESIS

Abbreviations

Developmental Anomaly

Chronic obstructive pulmonary disease (COPD)

Definitions

Pulmonary lobule

Composed of respiratory bronchiole, alveolar ducts, and alveoli Gas exchange unit of lung Terminal bronchiole: Final portion of conducting system COPD: Group of airway diseases causing dyspnea and characterized by airflow limitation, with considerable overlap between them Emphysema: Defined anatomically Abnormal, permanent enlargement of airspaces distal to terminal bronchioles Accompanied by destruction of airspace walls No obvious component of fibrosis Chronic bronchitis: Defined clinically Chronic productive cough for 3 months in 2 successive years Often have repeated respiratory tract infections Asthma: Not all authors include asthma as part of COPD; early on there is no fixed anatomic lesion Chronic airway disorder with variable and recurring episodes of dyspnea and wheezing Inflammation (often eosinophilic), mucus production, bronchoconstriction Longstanding, severe cases can develop fixed airway changes similar to chronic bronchitis Many patients with COPD show elements of both chronic bronchitis and emphysema

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Chronic cor pulmonale is shown. Cross section of the ventricles reveals marked right ventricular hypertrophy . The right and left ventricle are virtually the same thickness.

Congenital -1-antitrypsin deficiency

Emphysema and cirrhosis Early onset of onset of emphysema Panacinar pattern of emphysema Sometimes family history of emphysema ~ 1-5% of COPD patients Mutations in SERPINA1 gene; autosomal recessive -1-antitrypsin produced in liver Protects against protease activity

Environmental Exposure Cigarette smoking

80% of COPD patients in USA have smoking history But < 20% of smokers develop COPD 20% of COPD patients are never smokers Other unidentified genetic and environmental factors must be involved Amount and duration of cigarette smoking contribute to severity Biomass fuel use for heating and cooking Wood &/or dung Particularly in developing world Workplace inhaled irritants Agricultural: Organic dusts Industrial: Metallic fumes (e.g., cadmium, aluminum) Mining: Coal, heavy metals Air pollution COPD more common in urban settings than rural

CLINICAL ISSUES Epidemiology Incidence

5% of USA population affected

Key Facts Terminology

COPD: Spectrum of pulmonary diseases that produces dyspnea and is characterized by airflow limitation Emphysema: Airspace destruction distal to terminal bronchioles without significant fibrosis Chronic bronchitis: Productive cough for 3 months in 2 successive years without other explanation Asthma: Episodic dyspnea and wheezing with inflammation, mucus production, and inflammation (eosinophilic) Considerable clinical and pathological overlap between these 3rd leading cause of death in USA Cigarette smoking is most important etiologic agent in USA

3rd most common cause of death in USA 120,000 deaths per year Age Considerable overlap between emphysema and chronic bronchitis Chronic bronchitis: 40-45 years Emphysema: 50-75 years Gender Historically more prevalent in men Increased incidence in women in last 2 decades Possibly result of increased cigarette smoking, which peaked in women 10 years later than in men Women have more severe symptoms with same cigarette exposure Women: exposure to biomass cooking fuels in developing world 80% of never-smokers with COPD are women Asthma Increases risk for emphysema and chronic bronchitis True even after correction for smoking history

Presentation

Typical emphysema: "Pink puffer"

Thin Pulmonary hyperinflation Normal or near normal PaO2, normal or PCO2: No cyanosis Destruction of airspaces and associated capillaries Little ventilation/perfusion (VQ) mismatch Less often show signs of right-sided heart failure Typical chronic bronchitis: "Blue bloater" Heavy PAO , PCO : Cyanosis Airway obstruction by mucus; no loss of capillaries Marked VQ mismatch Cor pulmonale with edema and signs of right heart failure Prone to sleep apnea "Pink puffer" and "blue bloater" are extremes of clinical spectrum

Other inhaled irritants (industrial particulates, agricultural dusts, biomass fuel) are also implicated -1-antitrypsin is a rare cause of emphysema and hepatic cirrhosis Autopsy suggestions Consider checking for pneumothorax before opening thorax Look for changes of chronic cor pulmonale, right ventricular hypertrophy Look for evidence of right heart failure & associated changes (hepatosplenomegaly, ascites) Look for evidence of pulmonary hypertension If emphysema is accompanied by hepatic cirrhosis, consider -1-antitrypsin deficiency

Most COPD patients have elements of both

Asthma

Episodic occurrence of dyspnea and wheezing Known allergic or other types of triggers in some patients Reversible spontaneously or with treatment No characteristic fixed anatomic defect early in disease course

Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Laboratory Tests

Abnormal spirometry

FEV1: Forced expiratory volume (FEV) in 1 second Typically < 80% of predicted FEV1/FVC: FEV1 as a fraction of total forced vital capacity Typically < 0.7 Obstruction to airflow caused by increased airway resistance and airway collapse Polycythemia and hemoglobin and hematocrit in hypoxemic patients EKG: Right ventricular hypertrophy in patients with cor pulmonale

IMAGE FINDINGS Radiographic Findings

Plain films are not sensitive; symptomatic patients may have normal chest films

Emphysema

Hyperinflated lungs Flattened diaphragms Large retrosternal air space Chronic bronchitis Nonspecific changes Increased bronchial markings and cardiomegaly

CT Findings

High-resolution CT much more sensitive than plain films for emphysema Can distinguish patterns of emphysema

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Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC OBSTRUCTIVE PULMONARY DISEASE However, 20% of pathologically proven cases show negative CT scans Chronic bronchitis Bronchial wall thickening and enlarged vessels

MACROSCOPIC FEATURES External Examination

Barrel chest: anteroposterior (hyperinflation) Prominent accessory muscles of respiration and angle of Louis

Cyanosis (but not typically clubbing) Edema in those with right heart failure Yellow discoloration of fingertips in smokers Changes secondary to "tripod posture" (sitting forward with elbows on thighs or tabletop) Dahl sign: Symmetrical slanted calluses or discolorations on thighs Calluses on forearms or olecranon bursitis Skin changes in patients on chronic steroids Thin, easily torn skin with bruising

Internal Examination Body cavities

Pneumothorax should be considered in patients with emphysema Incise pleura under water seal prior to opening thorax Ascites in patients with right heart failure Hyperinflated lungs obscure heart Anthracotic mediastinal lymph nodes

Organ Examination Lungs

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Emphysema Bullous emphysema: Airspaces > 1 cm; often apical Chronic bronchitis Mucus in airways Asthma Hyperinflated lungs; may show impressions from ribs Tenacious mucus plugs in bronchi and bronchioles Heart: Cor pulmonale Right ventricular hypertrophy in chronic cor pulmonale Acute cor pulmonale (e.g., in pulmonary embolus or ARDS) characterized by right ventricular dilatation Pulmonary arteries may show evidence of pulmonary hypertension Yellow atherosclerotic plaques Liver Hepatomegaly and centrilobular congestion ("nutmeg liver") in patients with heart failure Cirrhosis in patients with -1-antitrypsin deficiency Spleen Splenomegaly in patients with heart failure

MICROSCOPIC PATHOLOGY Histologic Features

Emphysema: Destruction of airspaces; 3 patterns with much overlap Centriacinar Affects terminal bronchiole with relative sparing of peripheral respiratory lobule Most pronounced in apices of upper lobes and superior segments of lower lobes Most common type Most strongly associated with cigarette smoking Panacinar Affects entire respiratory lobule Most pronounced in lung bases Can be associated with -1-antitrypsin deficiency and methylphenidate injection Paraseptal Most pronounced in subpleural locations including lung fissures Can lead to bullous formation and pneumothorax Chronic bronchitis Hyperplasia of peribronchial mucus glands Reid index: Ratio of thickness of mucus gland layer to thickness of bronchial wall from basement membrane to cartilage Normally < 0.4 Increased in chronic bronchitis Goblet cell metaplasia of bronchial epithelium Peribronchial chronic inflammation Bronchiolar mucus and exudate Asthma Thickened bronchial basement membrane Bronchial edema and inflammation Inflammation typically eosinophil rich Enlarged bronchial mucus glands Bronchial smooth muscle hypertrophy Liver Centrilobular congestion with heart failure -1-antitrypsin deficiency Cirrhosis, cholestasis, cholangitis Periportal globules of PAS positive material (accumulated -1-antitrypsin in hepatocyte endoplasmic reticulum)

SELECTED REFERENCES 1.

3. 4. 5.

Aryal S et al: Influence of sex on chronic obstructive pulmonary disease risk and treatment outcomes. Int J Chron Obstruct Pulmon Dis. 9:1145-1154, 2014 Kim V et al: Chronic bronchitis and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 187(3):228-37, 2013 Nussbaumer-Ochsner Y et al: Systemic manifestations of COPD. Chest. 139(1):165-73, 2011 Silva GE et al: Asthma as a risk factor for COPD in a longitudinal study. Chest. 126(1):59-65, 2004 Tomashefski JF Jr et al: The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the national registry for individuals with Severe Deficiency of Alpha-1 Antitrypsin. Hum Pathol. 35(12):1452-61, 2004

Gross and Microscopic Images (Left) The cut surface of this lung shows markedly dilated airspaces in the case of emphysema. (Right) A closeup view of the cut surface of lung shows prominent bronchi projecting slightly above the surface of the lung tissue like tent poles.

(Left) Histologic section of emphysematous lung shows abnormally large alveoli with alveolar septa that appear to float or end blindly with club-like tips . (Right) This in situ photograph of a patient dying of an acute asthmatic episode shows hyperinflated lungs with rib impressions . Note the tan-pink color and lack of anthracotic pigment.

Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

(Left) This lung was taken from a patient who died during an acute asthmatic episode. The bronchial tree is opened to show copious, thick mucus . (Right) Close-up view of an opened pulmonary artery shows yellow atherosclerotic plaques , an indication of pulmonary hypertension. COPD with cor pulmonale is a common cause of pulmonary hypertension.

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Disease Process Approach to Autopsy: Other Common Hospital Death

VENTILATOR DEPENDENT RESPIRATORY FAILURE

Gross photograph shows organizing diffuse alveolar damage in a patient with connective tissue disease and prolonged mechanical ventilation. The lung shows tan areas of consolidation .

TERMINOLOGY Abbreviations

Ventilator-dependent respiratory failure (VDRF)

Definitions

Failure to wean from mechanical ventilation after a

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defined period of time Autopsied hospital population includes those who die while on mechanical ventilation and those who die shortly after terminal extubation or discontinued mechanical ventilation Ventilator-induced lung injury refers to histologic findings associated with mechanical ventilation: Hyaline membranes, increased vascular permeability, pulmonary edema, and inflammatory cell infiltrates Note that these findings are characteristic of diffuse alveolar damage related to any number of initiating etiologies that may have led to need for mechanical ventilation It is therefore difficult to separate out cause(s) leading to mechanical ventilation from effects of treatment 1994 American-European Consensus Conference on ARDS set forth clinical criteria for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in order to provide a more uniform approach for further study (a.k.a. the Berlin Definition) From a histologic perspective, patients with clinical evidence of acute lung injury most often have histologic pattern of diffuse alveolar damage However, other histologic patterns may be seen, including acute fibrinous and organizing pneumonia (AFOP), acute eosinophilic pneumonia, and diffuse hemorrhage with capillaritis These criteria were revised in 2012 to stratify ARDS into 3 grades

Organizing diffuse alveolar damage is shown histologically, with diagnostic features of residual hyaline membranes and fibroblastic proliferation .

Term ALI was retained only for research purposes and not for clinical stratification Centers for Disease Control and Prevention has introduced new surveillance definitions for ventilatorassociated event that include all complications severe enough to result in sustained increases in ventilatory support Ventilator-associated infectious complications are included in this definition as are other complications such as excess fluid administration and adverse effects of opioid administration

ETIOLOGY/PATHOGENESIS Pathogenesis

Purpose of mechanical ventilation is to provide adequate gas exchange while resting respiratory muscles Ventilator strategies designed to reduce lung injury have been shown to decrease mortality in patients with ARDS; however, as is well known, morality is high, particularly in some groups of patients In a patient who dies with clinical diagnosis of ventilator-dependent respiratory failure, there are 4 major etiologic categories that may influence autopsy findings and may be superimposed on each other Initial inciting event that led to lung injury Frequent occurrence of what are now termed ventilator-associated events (VAEs) Direct effects of ventilator-induced lung injury Other comorbid conditions such as cardiac disease or liver failure, as well as others Regional lung overdistension is a critical factor in ventilator-induced lung injury Ventilation at high lung volumes results in alveolar rupture, air leaks, and barotrauma (pneumothorax, pneumomediastinum, and subcutaneous emphysema)

Key Facts Terminology

Ventilator-dependent respiratory failure (VDRF) is failure to wean from mechanical ventilation after a defined period of time

Etiology

4 major etiologic categories to consider in VDRF

Initial inciting event that led to lung injury Superimposed ventilator-associated complications such as infection Direct effects of ventilator-induced lung injury Other comorbid conditions

Clinical Issues

Most common cause of VDRF is an acute lung injury superimposed on severe chronic disease

Overdistension may also result in pulmonary edema, although exact mechanism is not completely understood Even at low lung volumes, there are effects caused by repetitive opening and closing of airways and respiratory units, effects on surfactant function, regional hypoxia, and intracellular/inflammatory mediators

CLINICAL ISSUES Presentation

Most common cause of VDRF is an acute lung injury superimposed on severe chronic disease It is possible for underlying chronic disease to be undiagnosed or obscured by the acute presentation Particularly true of older patients with pulmonary fibrosis in whom fibrosis may have been insidious in onset until time of an acute exacerbation A major clinical goal (and in some instances a postmortem examination goal) is to define or exclude underlying chronic disease De novo acute lung injury, occurring as either a primary respiratory disease or in setting of multiorgan system dysfunction, is also common and can also result in VDRF Other patients are ventilator dependent as a consequence of neuromuscular disorders or chest wall trauma

Prognosis

Even when normalization of arterial blood gases is achieved by mechanical ventilation, many patients die while on mechanical ventilation Ventilator strategies designed to reduce lung injury have been shown to decrease mortality in patients with ARDS Causes of mortality Barotrauma Oxygen toxicity Hemodynamic compromise

Macroscopic Pathology

Gross findings correlate with stage of diffuse alveolar damage

Mechanical ventilation may result in alveolar rupture, air leaks, and barotrauma (pneumothorax, pneumomediastinum, and subcutaneous emphysema)

Microscopic Pathology

Diffuse alveolar damage is the most common pattern associated with VDRF

Infection, either as a primary etiology or as a ventilator-associated complication, should be rigorously excluded with special stains and ancillary microbiology studies

Both ventilator-associated conditions and infectionrelated ventilator associated conditions are associated with prolonged mechanical ventilation and hospital death

MACROSCOPIC FEATURES

Disease Process Approach to Autopsy: Other Common Hospital Death

VENTILATOR DEPENDENT RESPIRATORY FAILURE

External Examination

If present, tracheostomy site should be examined for evidence of bleeding or infection

Other intensive monitoring devices are often present

Internal Examination

If present, appropriate positioning of endotracheal tube and chest tubes should be documented

Organ Examination

Lungs should be weighed prior to formalin inflation

It is not uncommon for combined lung weights to exceed 1,500 g Lung weights generally correlate with severity of respiratory failure and presence of diffuse alveolar damage Tracheal, mucosal, and mural changes consistent with prolonged intubation Pressure necrosis (mucosal ulceration and cartilage degeneration) Section to exclude infection (viral, bacterial, and fungal infections such as Aspergillus or Candida most likely) Important chronic diseases that may have contributed to ventilator dependence and that can be anatomically characterized include upper airway obstruction, obstructive lung disease, pulmonary fibrosis, ischemic cardiomyopathy, and direct traumatic (central or peripheral) neuromuscular injury Contributing factors that may be difficult to define anatomically but that can be supported by clinical history include critical illness neuromuscular abnormalities, metabolic or endocrine disorders, and therapy effects

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Disease Process Approach to Autopsy: Other Common Hospital Death

VENTILATOR DEPENDENT RESPIRATORY FAILURE Following fixation of lung, careful attention should

Pathologic Interpretation Pearls

MICROSCOPIC PATHOLOGY

Possibility of infection should be rigorously evaluated

Histologic Features

Identify underlying chronic disease(s) that may have

Diffuse alveolar damage (DAD) is the most common

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and rapid development of hypoxemic respiratory failure that requires prolonged mechanical ventilation Definition excludes patients with ARDS that can be attributed to an identifiable cause as well as patients with underlying fibrotic lung disease or systemic disorders known to be associated with lung involvement, e.g., connective tissue disease Many patients describe a URI/viral-like prodrome and a nonproductive cough This prodrome may precede shortness of breath by 1 week to 2 months Autopsy sections usually show enlarged and remodeled airspaces that resemble the honeycomb change of UIP and reflect progressive disease, but fibroblastic proliferation along with collagen deposition should still be conspicuous within walls of air spaces

be paid to the possibility of underlying chronic lung disease In addition to characterizing acute changes and excluding infection, sections should be taken of more fibrotic areas Gross findings correlate with stage of diffuse alveolar damage In early phase, lungs are firm, heavy, and have a relatively homogeneous dark red appearance In later phase, lungs are very heavy with irregular areas of dense consolidation and fibrosis If patient was maintained on mechanical ventilation for a long period of time, there will be progressive fibrosis that may result in some "cobblestoning" of pleural surface Extensive peripheral cyst formation consistent with honeycombing is a finding that suggests possibility of underlying chronic fibrotic lung rather than acute interstitial pneumonia (AIP) Evidence of mechanical ventilation such as pulmonary interstitial emphysema and small cysts as well as more consequential findings such as pneumothorax

pattern associated with VDRF Criteria for the diagnosis of DAD include the presence of hyaline membranes in addition to at least 1 of the following Intraalveolar edema, type 1 alveolar cell necrosis, type 2 alveolar pneumocyte hyperplasia covering denuded alveolar-capillary membrane, interstitial fibroblastic/myofibroblastic proliferation of fibroblasts, or organizing interstitial fibrosis Other histologic patterns that resemble clinical picture of ARDS and VDRF but are not associated with classic DAD histopathology include bacterial or viral pneumonia, diffuse interstitial pneumonia, pulmonary hemorrhage, or tumor infiltration Less common histologic patterns associated with acute lung injury Acute eosinophilic pneumonia is often recognized clinically and treated appropriately with good response It is therefore a very uncommon cause of VDRF Once steroid treatment is instituted, it may be very difficult to identify eosinophils Alveolar hemorrhage should be considered where there is marked coarse hemosiderin and capillaritis Acute fibrinous and organizing pneumonia is characterized by diffuse intraalveolar fibrin balls as opposed to classic hyaline membranes Acute interstitial pneumonia (AIP) also should be considered within differential diagnosis of diffuse alveolar damage and VDRF AIP is an idiopathic interstitial lung disease that is clinically characterized by sudden onset of dyspnea

DIAGNOSTIC CHECKLIST Diffuse alveolar damage, often in different phases, is a common finding

with special stains and ancillary microbiology studies contributed to ventilator dependence

SELECTED REFERENCES 1.

2. 3.

4. 5. 6.

Lewis SC et al: Risk factors for ventilator-associated events: a case-control multivariable analysis. Crit Care Med. 42(8):1839-48, 2014 Slutsky AS et al: Ventilator-induced lung injury. N Engl J Med. 370(10):980, 2014 ARDS Definition Task Force et al: Acute respiratory distress syndrome: the Berlin Definition. JAMA. 307(23):2526-33, 2012 Ambrosino N et al: The difficult-to-wean patient. Expert Rev Respir Med. 4(5):685-92, 2010 Beasley MB: The pathologist’s approach to acute lung injury. Arch Pathol Lab Med. 134(5):719-27, 2010 Wunsch H et al: The epidemiology of mechanical ventilation use in the United States. Crit Care Med. 38(10):1947-53, 2010 Bernard GR et al: The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 149(3 Pt 1):818-24, 1994

Gross and Microscopic Features of VDRF and Underlying Lung Pathology (Left) Gross image shows organizing diffuse alveolar damage with tan areas of consolidation and some more preserved lung parenchyma . (Right) This lung demonstrates organizing diffuse alveolar damage in a mechanically ventilated patient who also received extracorporeal membrane oxygenation (ECMO). The parenchyma is diffusely consolidated and red brown in appearance.

(Left) Gross image shows diffuse alveolar damage in a patient who had a prolonged course of mechanical ventilation and the additional complication of a chest tube in the oblique fissure . (Right) The extensive cobblestoning of the pleural surface of this lung from a patient with VDRF indicated underlying pulmonary fibrosis.

Disease Process Approach to Autopsy: Other Common Hospital Death

VENTILATOR DEPENDENT RESPIRATORY FAILURE

(Left) The cut surface of this lung shows honeycombing in a patient with underlying pulmonary fibrosis and ventilator dependent respiratory failure. (Right) This patient with VDRF had acute interstitial pneumonia with diffusely enlarged and remodeled airspaces . There is conspicuous fibroblastic proliferation and collagen deposition within the alveolar walls .

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Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC LIVER FAILURE

The cut surface of this liver with micronodular cirrhosis due to alcoholic liver disease shows innumerable small nodules

3 mm in diameter. (Courtesy D. Rubin, MD.)

TERMINOLOGY Abbreviations

Chronic liver failure (CLF)

Definitions

Liver dysfunction due to diseases that cause progressive destruction and regeneration of parenchyma over weeks to years, leading to fibrosis, disruption of the vascular architecture, and cirrhosis

ETIOLOGY/PATHOGENESIS Common Etiologies of CLF/Cirrhosis Alcoholic liver disease

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CLF in 15-20% of chronic heavy alcoholics Women susceptibility and mortality Chronic viral hepatitis infection CLF in ~ 25-30% of chronic hepatitis C and hepatitis BD Rarely hepatitis E in immunosuppressed Nonalcoholic fatty liver disease (NAFLD) ~ 30% of general population, CLF in ~ 20% with steatohepatitis Associated with diabetes mellitus, dyslipidemia, obesity, drugs (e.g. amiodarone, corticosteroids, tamoxifen) Autoimmune hepatitis Females > males; ~ 30% with cirrhosis at time of diagnosis Biliary diseases Primary biliary cirrhosis (PBC) Females >> males; CLF in ~ 15% at 5 years Primary sclerosing cholangitis (PSC) Males > females; 60-80% have inflammatory bowel disease ~ 15% with cirrhosis at time of diagnosis; risk of cholangiocarcinoma

This cirrhotic liver has an intact transjugular intrahepatic portosystemic shunt (TIPS) between the middle hepatic vein and the right portal vein . (Courtesy D. Rubin, MD.)

Secondary biliary cirrhosis Chronic large duct obstruction by tumors, stones, strictures, parasites, extrahepatic biliary atresia Metabolic disorders Hemochromatosis Primary/hereditary: Many types of mutations with variable penetrance; most common is C282Y HFE mutation, usually autosomal recessive Secondary: Due to multiple blood transfusions, chronic hemolysis, enteral/parenteral overload, cirrhosis of any cause Wilson disease Copper accumulation due to mutations in ATP7B gene; autosomal recessive - -antitrypsin (A1AT) deficiency Accumulation of abnormal A1AT protein

cirrhosis and emphysema; autosomal recessive Drug/toxin-induced injury Steatohepatitis (e.g., methotrexate, estrogens) Chronic hepatitis (e.g., antibiotics, doxorubicin) Immune-mediated hepatitis (e.g., statins, minocycline) Chronic cholestasis (e.g., total parenteral nutrition, antibiotics) Venous outflow obstruction Chronic outflow obstruction due to hepatic vein thrombosis (Budd-Chiari syndrome), congestive heart failure, constrictive pericarditis

Pathogenesis of Complications of CLF/ Cirrhosis Portal hypertension (HTN)

Present in nearly all cirrhotics, due to increased resistance to portal blood flow secondary to scarring, distortion of vascular architecture, formation of intrahepatic shunts, and endothelial dysfunction collateral vessel formation esophageal/gastric varices, portal hypertensive gastropathy, caput

Key Facts Terminology

Chronic liver failure: Result of liver disease that causes progressive destruction and regeneration of parenchyma over weeks to years, leading to fibrosis, disruption of vascular architecture, and cirrhosis

Etiology

Alcoholic/nonalcoholic fatty liver disease Chronic viral hepatitis infection, autoimmune hepatitis Biliary diseases: Primary biliary cirrhosis, primary sclerosing cholangitis Metabolic disorders: Wilson disease, hemochromatosis, --antitrypsin deficiency Drug/toxin-induced injury Venous outflow obstruction

medusae, and splenomegaly hypersplenism and thrombocytopenia Ascites (due to portal HTN + splanchnic vasodilation) Refractory (diuretic-resistant) treated with transjugular intrahepatic portosystemic shunt (TIPS) or peritoneovenous shunt Spontaneous bacterial peritonitis (SBP): Infection of ascites fluid sepsis Hepatic encephalopathy ~ 70% of cirrhotics, in neuropsychiatric function caused by toxins produced by intestinal bacteria in portal venous blood Due to inability of hepatocytes to metabolize toxins and to portosystemic shunting (varices or TIPS procedure) Hepatocellular carcinoma: Risk varies by cause of cirrhosis (higher in hepatitis B and C infection) Hepatorenal syndrome (portal HTN + splanchnic vasodilation + Na + retention + renal vasoconstriction): Incidence ~ 8% of cirrhotics renal failure Type 1 hepatorenal syndrome: Rapid deterioration of renal function usually precipitated by SBP Type 2 hepatorenal syndrome: Remains stable for longer; usually associated with refractory ascites Hepatopulmonary syndrome: ~ 4-50%, hypoxemia due to intrapulmonary arteriovenous dilatations leading to ventilation/perfusion mismatch, diffusionperfusion defects, and shunting of blood from pulmonary arteries to veins Portal vein thrombosis: ~ 15-25%, due to stasis or infection; can worsen portal HTN Hyperestrogenemia spider angiomas, palmar erythema, gynecomastia, hypogonadism synthetic function: Hypoalbuminemia edema, coagulopathy bleeding, protein malnutrition

cachexia

Clinical Issues

Complications: Portal hypertension, ascites, encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, spontaneous bacterial peritonitis, hepatocellular carcinoma, portal vein thrombosis, coagulopathy

Macroscopic Pathology

Cirrhosis (micronodular, macronodular, or mixed), masses

Microscopic Pathology

Cirrhosis: Regenerative nodules of hepatocytes surrounded by fibrous bands without central veins

Top Differential Diagnoses Acute liver failure

CLINICAL ISSUES Epidemiology Incidence

Cirrhosis is 9th leading cause of death in USA

Presentation

Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC LIVER FAILURE

Abdominal pain, anorexia, fatigue, pruritus, fever, arthralgia, weight loss, easy bruising/bleeding, dyspnea

Jaundice, abdominal girth, osteoporosis, mental status changes, asterixis, oliguria

Important elements of chart review: History of alcohol use, intravenous drug use, blood/body fluid exposure, medications, family history of liver disease, comorbid conditions

Laboratory Tests

transaminases, bilirubin, alkaline phosphatase, gamma-glutamyl transferase, alpha-fetoprotein

Hyperammonemia, hypoalbuminemia, hyperglycemia, hyponatremia, serum creatinine, creatinine clearance prothrombin and partial thromboplastin times, international normalized ratio, thrombocytopenia Serum ascites albumin gradient > 1.1 g/dL; > 250 polymorphonuclear cells/mm in ascites fluid (SBP) (+) blood, urine, ascites fluid cultures (+) viral hepatitis titers/DNA/RNA (+) antinuclear and anti-smooth muscle antibody (autoimmune hepatitis type 1); + anti-liver kidney microsomal and anti-liver cytosol type 1 antibody (autoimmune hepatitis type 2), IgG (+) antimitochondrial antibody and IgM (PBC); (+) perinuclear antineutrophil antibodies (p-ANCA) (PSC) fasting transferrin saturation, ferritin, iron-binding capacity (hemochromatosis) serum A1AT levels; serum ceruloplasmin, urine copper, and hemolytic anemia (Wilson disease)

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Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC LIVER FAILURE Prognosis

Annual mortality ranges from 1-57% depending on level of decompensation

Mortality of complications

Bleeding esophageal/gastric varices 30-day mortality ~ 15-20% Hepatic encephalopathy 1-year mortality ~ 64% Type 1 hepatorenal syndrome: Almost all die within 10 weeks Type 2 hepatorenal syndrome: Median survival: 3-6 months Infection: Most common types are SBP, urinary tract infections, pneumonia, skin infections; 30% die within 1 month, another 30% die within 1 year Coagulopathy massive gastrointestinal bleeding: Death within weeks to months HCC 5-year mortality ~ 10-50%

MICROSCOPIC PATHOLOGY IMAGE FINDINGS Radiographic Findings

Hepatic atrophy, hepatomegaly, nodularity, fatty change, masses

Evidence of portal hypertension: Splenomegaly, collateral vessel formation, hepatofugal flow in portal vein, ascites

Cholangiography

Bile duct stenosis, strictures, stones, masses "Beading" due to strictures and dilatations and "pruned tree" appearance due to intrahepatic branching (PSC)

MACROSCOPIC FEATURES External Examination

Scleral icterus, jaundice, spider angiomas, palmar erythema, prominent periumbilical vessels (caput medusae), bronze skin (hemochromatosis) Gynecomastia, temporal wasting, finger clubbing, cyanosis Evidence of interventional/surgical procedures

Internal Examination

Ascites, pleural/pericardial effusions

Organ Examination Liver

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Portal hypertensive gastropathy ("mosaic"-appearing friable gastric mucosa with vascular ectasia), hemorrhagic gastritis Pancreas: Firm fibrotic atrophic parenchyma, dilated ducts, stones, pseudocysts Lungs: Small vessel dilatations, emphysema, consolidation Other organs Cardiomegaly (systemic or pulmonary hypertension), cardiomyopathy (alcohol/ hemochromatosis) Testicular atrophy and gynecomastia (hyperestrogenism) Splenomegaly (portal hypertension), bile nephrosis (green-yellow-appearing kidneys, especially medulla) Cerebral and cerebellar atrophy (chronic alcoholism)

Hepatomegaly, yellow greasy cut surface, green discoloration, masses necrosis Nodules surrounded by fibrous tissue: Micronodular ( 3 mm), macronodular, or mixed Congested "nutmeg" liver, thrombi in hepatic or portal veins Dilated bile ducts fibrotic walls, stenosis, inspissated bile, mucosal ulcers, chole-/ hepatolithiasis Status of TIPS: Shunt between branch of hepatic and portal vein Gastrointestinal tract Esophageal/gastric varices (dilated, engorged submucosal vessels), erosions, ulcers

Histologic Features Hepatic findings

Cirrhosis: Regenerative nodules of hepatocytes surrounded by fibrous bands without central veins, dysplastic nodules, HCC Biliary-type cirrhosis: "Jigsaw puzzle"-like with irregular nodules surrounded by edematous bands of fibrous tissue seen in PBC, PSC, and secondary biliary cirrhosis Venocentric-type cirrhosis: Central vein to central vein fibrosis with sparing of portal tracts Alcoholic liver disease Steatosis, steatohepatitis (ballooning degeneration of hepatocytes, necrosis and pericellular inflammation), neutrophilic infiltrates, MalloryDenk bodies, cholestasis Foamy degeneration (microvesicular steatosis), sclerosing hyaline necrosis (perivenular necrosis + fibrosis) Pericellular fibrosis, usually micronodular cirrhosis Chronic viral hepatitis C infection: Lymphoid aggregates in portal tracts, variable interface and lobular inflammatory activity, naked acidophil bodies, macronodular or mixed cirrhosis Chronic viral hepatitis B D infection: Chronic hepatitis, variable interface and lobular inflammatory activity, ground-glass hepatocytes, "sanded" nuclei, macronodular or mixed cirrhosis NAFLD: Steatosis, steatohepatitis (mainly lymphocytes neutrophils), Mallory-Denk bodies, glycogenated nuclei, perivenular/ pericellular fibrosis Autoimmune hepatitis: Portal and interface lymphoplasmacytic infiltrates, perivenular inflammation/necrosis, hepatocyte rosettes Metabolic disorders Hemochromatosis: Hepatocellular iron deposition (begins in zone 1), bile duct iron deposition, portal inflammation and fibrosis cirrhosis, Kupffer cell siderosis (usually secondary hemochromatosis)

Wilson disease: Variable portal inflammation, periportal ductular reaction, steatosis, periportal glycogenated nuclei, Mallory-Denk bodies, hepatocellular copper accumulation (focal/patchy) A1AT deficiency: Eosinophilic periodic acidSchiff with diastase (PAS-D)-resistant globules in periportal hepatocytes ([+] immunostain for A1AT), steatosis, portal lymphocytic infiltrates PBC Nonsuppurative granulomatous destructive cholangitis (florid duct lesion) Associated portal inflammation plasma cells and eosinophils, variable interface activity, ductular reaction Cholate stasis ("feathery" degeneration of hepatocytes), ductopenia PSC Portal inflammation, periportal ductular reaction, "onion-skin" concentric periductal fibrosis Inflammation, degenerative changes, and atrophy of bile ducts, "fibro-obliterative" lesions (bile ducts replaced by whorls of fibrous scar tissue), ductopenia Large ducts with ulcers, xanthogranulomatous inflammation, and fibrous scars, biliary intraepithelial neoplasia (BilIN), cholangiocarcinoma Secondary biliary cirrhosis Features of large bile duct obstruction (portal tract edema, periportal ductular reaction, associated neutrophils chronic inflammation) Canalicular cholestasis, cholate stasis, bile lakes, bile infarcts Venocentric-type cirrhosis Venous outflow obstruction: Centrilobular congestion, sinusoidal dilatation and congestion, centrilobular hepatocyte atrophy/necrosis, peliosis, perivenular/perisinusoidal fibrosis Other organ findings Portal hypertensive gastropathy (dilated, tortuous submucosal vessels in gastric body), erosive/ hemorrhagic gastritis (alcohol use), chronic active colitis/inflammatory bowel disease (PSC) Chronic pancreatitis with interstitial fibrosis, loss of acini and ducts, islet aggregation, dilated ducts concretions Iron deposition in pancreas, adrenal glands, myocardium (hemochromatosis) Panlobular emphysema (AAT deficiency), pneumonia, wall thickness of pulmonary veins and capillaries (hepatopulmonary syndrome) Copper accumulation in brain, kidneys, cornea (Wilson disease) Type 2 astrocytosis in cerebral cortex and basal ganglia (hepatic encephalopathy), cerebellar atrophy with loss or Purkinje cells in vermis (chronic alcoholism), peripheral neuropathy Wernicke encephalopathy (areas of hemorrhage and necrosis in mamillary bodies and walls of 3rd and 4th ventricles)

Korsakoff syndrome (healed Wernicke lesions with macrophage infiltration and cyst formation [thiamine deficiency in chronic alcoholism]) Pigmented yellow green casts in distal tubules and collecting ducts and acute tubular injury (hepatorenal syndrome)

ANCILLARY TESTS Histochemistry

Trichrome to evaluate fibrosis Rhodanine (copper) and Victoria blue/orcein (copperbinding protein) in Wilson disease, also present in chronic cholestatic diseases Iron stain, PAS-D (A1AT)

Immunohistochemistry

Hepatitis B surface and core antigens, A1AT CK7 highlights bile duct epithelium and hepatocytes with chronic cholestasis

Microbiology

Postmortem blood, urine, ascites fluid, pleural/ pericardial fluid, tissue cultures

DIFFERENTIAL DIAGNOSIS

Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC LIVER FAILURE

Acute Liver Failure

Similar clinical presentation but for < 26 weeks duration without history or signs of underlying chronic liver disease Some similar etiologies (hepatitis B D, autoimmune hepatitis, Wilson disease, drug induced) Radiographic findings: Hepatic atrophy or hepatomegaly, surface nodularity due to alternating necrosis and regeneration, evidence of portal hypertension Macroscopic findings: Necrosis and regenerative nodules without fibrosis/cirrhosis Microscopic findings: Varying degrees of necrosis, parenchymal collapse, ductular reaction, regeneration, no bridging fibrosis

REPORTING CRITERIA Final Report Should Include

Etiology of CLF, presence of complications, effects on other organs

Whether it was cause of death or contributing factor Implications for living family members (hereditary diseases)

SELECTED REFERENCES 1. 2. 3.

Tsochatzis EA et al: Liver cirrhosis. Lancet. 383(9930):1749-61, 2014 Liberal R et al: Autoimmune hepatitis: a comprehensive review. J Autoimmun. 41:126-39, 2013 Panella M et al: Unsuspected hereditary hemochromatosis at forensic autopsy: its presentation, confirmation, and implications. Am J Forensic Med Pathol. 32(1):20-4, 2011

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CHRONIC LIVER FAILURE

Causes of Chronic Liver Failure (Left) This liver shows the characteristic features of alcoholic steatohepatitis: Steatosis , ballooning degeneration of hepatocytes with abundant Mallory-Denk bodies , and pericellular neutrophilic inflammation . (Right) Chronic autoimmune hepatitis is characterized by lymphoplasmacytic infiltrates involving the portal tracts and periportal regions. Lymphocytes and plasma cells surround individual hepatocytes at the interface .

(Left) Periodic acid-Schiff stain with diastase digestion (PASD) highlights numerous - antitrypsin globules (bright pink) in the cytoplasm of periportal hepatocytes in this case of chronic liver failure due to - -antitrypsin deficiency. (Right) This iron stain shows diffuse hepatocellular siderosis (blue granules) without significant Kupffer cell siderosis in this patient with hereditary hemochromatosis.

(Left) The "florid duct lesion" is characteristic of primary biliary cirrhosis. This portal tract contains a poorly formed periductal granuloma with associated chronic inflammation including eosinophils and lymphocytes infiltrating the residual, nearly destroyed bile duct . (Right) The fibro-obliterative lesion is a characteristic finding in primary sclerosing cholangitis. The bile duct in this portal tract has been replaced by a round, fibrous scar .

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Complications of Chronic Liver Failure (Left) Esophageal and gastric varices are a common complication of portal hypertension due to cirrhosis and may cause massive gastrointestinal bleeding. (Courtesy D. Rubin, MD.) (Right) Portal vein thrombosis occurred in a patient with cirrhosis due to chronic hepatitis B infection.

(Left) Spider angiomas occur in hyperestrogenemic states such as cirrhosis. They appear as a red papule (dilated arteriole) with thin veins radiating outward from the center . These occurred in a patient with cirrhosis due to chronic hepatitis C infection. (Right) Scleral icterus is caused by hyperbilirubinemia in this patient with cirrhosis due to chronic viral hepatitis C infection.

Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC LIVER FAILURE

(Left) Splenomegaly is a common complication of portal hypertension. This spleen from a patient with alcoholic cirrhosis weighed 460 g (normal weight: 150-200 g). (Right) Hepatocellular carcinoma in a patient with chronic hepatitis B infection appears as multinodular pale tan masses . The background hepatic parenchyma is not cirrhotic. (Courtesy D. Rubin, MD.)

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Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC RENAL FAILURE

PAS stain highlights mesangial matrix and the nodules in diabetic nephropathy are strongly positive. The nodules are composed mainly of matrix with minimal or no cellular proliferation.

TERMINOLOGY Abbreviations

Chronic renal failure (CRF)

Synonyms

Chronic kidney disease (CKD)

Definitions

Renal function deterioration with glomerular filtration rate (GFR) < 60 mL/minute per 1.73 m &/or kidney damage for 3 months due to diseases causing destruction of parenchyma leading to fibrosis, glomerulosclerosis, and vascular damage

ETIOLOGY/PATHOGENESIS Glomerular Diseases

Most types of glomerulonephritis can progress and cause CRF in variable time interval Membranous glomerulopathy: ~ 33% progress to end-stage renal disease (ESRD) Primary focal segmental glomerulosclerosis: Significant fraction of cases progress to ESRD IgA nephropathy: Progresses to ESRD in ~ 30% of cases Membranoproliferative glomerulonephritis: Slow progress to ESRD in ~ 10 years Lupus nephritis: Median progression to ESRD is 10 years in ~ 25% of cases Fibrillary glomerulopathy: 40-50% progress to ESRD in 2-4 years Anti-GBM crescentic glomerulonephritis: Most cases progress to ESRD

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Tubular/Interstitial Diseases Chronic pyelonephritis

In arterionephrosclerosis, solidified-type global sclerosis is characterized by corrugation of the glomerular basement membranes involving the entire glomerular tuft.

Chronic interstitial nephritis (e.g., urate nephropathy, lithium toxicity, oxalate nephropathy, 2,8 dihydroxyadenuria) Chronic infections Tuberculosis Xanthogranulomatous pyelonephritis Malakoplakia Autosomal dominant adult polycystic kidney disease (ADPKD) Mutations in polycystin 1 (PKD1) 16p13.3 and polycystin 2 (PKD2) 4q21

Vascular Diseases

Hypertensive nephrosclerosis: Vascular and parenchymal damage associated with high blood pressure Renal artery stenosis secondary to atherosclerosis, fibromuscular dysplasia, dissecting aneurysm, vasculitis, retroperitoneal fibrosis, and neurofibromatosis

Metabolic

Diabetic nephropathy

Paraprotein-Associated

Amyloidosis (e.g., light chain [AL], secondary amyloidosis [AA], transthyretin, and others)

Light/heavy chain immunoglobulin deposition disease

CLINICAL ISSUES Epidemiology Incidence

Glomerular diseases affect 12-16% of patients with CRF ADPKD is ~ 3% of patients with CRF Hypertensive nephrosclerosis is 29-38% of patients with CRF

Key Facts Terminology

Renal function deterioration with glomerular filtration rate (GFR) < 60 mL/min per 1.73 m &/ or kidney damage for 3 months due to diseases causing destruction of parenchyma leading to fibrosis, glomerulosclerosis, and vascular damage

Clinical Issues

Glomerular diseases affect 12-16% of patients with CRF ADPKD is ~ 3% of patients with CRF Hypertensive nephrosclerosis is 29-38% of patients with CRF Diabetes nephropathy is ~ 50% of patients with CRF and 1/3 of patients in dialysis

Diabetes nephropathy in ~ 50% of patients with CRF and 1/3 of patients in dialysis Age Glomerular diseases present in children and young adults ADPKD become symptomatic at 40-50 years Hypertensive nephrosclerosis presents in adults and older patients Diabetic nephropathy may present in young adults in type 1 and in older adults in type 2

Presentation

Glomerular diseases

Hematuria Proteinuria Hypertension Progressive increase of creatinine Metabolic abnormalities Tubular/interstitial diseases Chronic pyelonephritis/other infections History of recurrent infections Urinary anomalies: Obstruction, nephrolithiasis, posterior urethral valves Back pain Fever Pyuria/bacteriuria Hypertension Increased creatinine Proteinuria usually nonnephrotic range Chronic interstitial nephritis Nonspecific urinary sediment abnormalities Proteinuria, nonnephrotic range Gradually progressive renal failure ADPKD Hypertension Hematuria Flank pain Infections Nephrolithiasis Cysts involving liver, pancreas, and spleen, and aneurysms in circle of Willis Hypertensive kidney disease

Progression to ESRD is variable depending upon etiology of renal disease

Microscopic Pathology

Varies depending on etiology of renal failure When process is advanced, it may not be possible to determine etiology

Ancillary Tests

Special stains (AFB, GMS) are contributory for specific diagnosis of infections

Panel including IgG, IgA, IgM, C3, C1, light chains, albumin, and fibrinogen is necessary in cases of glomerular diseases Electron microscopy should be performed in cases of glomerular diseases

Longstanding elevated blood pressure Proteinuria variable degree may be nephrotic Progressive renal failure Renal artery stenosis Renovascular hypertension Progressive renal failure Diabetic nephropathy Proteinuria initially in nonnephrotic range with progression to nephrotic proteinuria Progressive renal failure Hypertension Neuropathy Retinopathy

Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC RENAL FAILURE

Laboratory Tests

Serum creatinine Blood urea nitrogen (BUN) Cystatin C (CysC) -2-microglobulin Urinalysis: Albuminuria Urine cultures Antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), anti-GBM antibodies

Hepatitis C and B serologies Serum/urine protein electrophoresis

Treatment Drugs

Angiotensin converting enzyme (ACE) inhibitors Angiotensin receptor blockers (ARBs) Antihypertensive medication Antidiabetic medication Antibiotics Statins Renal replacement therapy Hemodialysis Peritoneal dialysis Transplantation

Prognosis

Glomerulonephritis progress to ESRD in variable interval time

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CHRONIC RENAL FAILURE Hypertension progression to ESRD is slow Diabetic nephropathy progress to ESRD in 5-10 years after proteinuria is present

ADPKD progresses to ESRD faster in type 1

IMAGE FINDINGS CT Findings

Asymmetrically or symmetrical contracted kidneys Coarse patchy cortical scars Blunting/deformity pyelocaliceal system In ADPKD, bilateral enlarged cystic kidneys

Angiography

Renal artery stenosis can be identified

MACROSCOPIC FEATURES External Examination

Sallow/yellow appearance of skin Muscle atrophy

Organ Examination Kidney

Glomerular diseases Marked reduction of kidney size External surface with granular appearance Tubular interstitial diseases Chronic pyelonephritis Kidney size may be reduced Irregular cortical scars with U-shaped broad base appearance overlying blunted/deformed calyces Renal poles are more involved Scars are demarcated from adjacent parenchyma Thinned cortex Chronic interstitial nephritis Kidney usually reduced in size and shrunken Chronic infections Renal tuberculosis: Initial lesions involve renal pelvis, calyces, and papillae; ulceration and caseous material can obstruct ureteropelvic junction causing hydronephrosis; cortical multiple small yellow nodules Xanthogranulomatous pyelonephritis: Kidney may be enlarged with yellow mass lesions that are usually unilateral involving pyelocalyceal regions Malakoplakia: Enlarged kidney with raised multiple yellow nodules distributed through parenchyma and pelvic lining ADPKD Markedly enlarged kidneys, bilateral Weight range from 4.5-10 lb Cobbled appearance of external surface Hypertensive nephropathy Reduction of kidney size Finely granular appearance of external surface Thinned cortex Renal artery stenosis Narrowing of renal artery Friable lipid debris, calcification, and dense fibrosis in atherosclerosis

Multiple ridges of hyperplastic muscle alternating with dilated segments with thin wall, in muscular dysplasia involving distal 2/3 of main renal artery Diabetic nephropathy Enlarged kidney in early stage Normal size or reduced size in advanced stage Irregular external surface Papillary necrosis with pyramid loss may be present Other organs Heart Congestive heart failure Atherosclerotic coronary artery disease with significant wall calcification Mitral valve annulus and aortic cusps calcification Uremic cardiomyopathy Pericarditis Sudden cardiac death (especially with dialysis) Lung Edema Uremic pneumonitis Gastrointestinal tract Mucosa inflammation, erosion, ulceration Angiodysplasia Ischemic changes Acute/chronic pancreatitis Central nervous system Ischemic/hemorrhagic infarcts Uremic encephalopathy Atherosclerosis Bones and joints Amyloid -2 microglobulin deposition Destructive arthropathy Bone cysts/fractures Osteitis fibrosa/osteomalacia

MICROSCOPIC PATHOLOGY Histologic Features Glomerular diseases

Variable mesangial/endocapillary proliferation seen in nonsclerotic glomeruli In advanced stage, global glomerulosclerosis is seen in all types of glomerular diseases Chronic pyelonephritis Tubular atrophy Dilated tubules with hyaline casts (thyroidization) Variable degree of interstitial mononuclear inflammation Interstitial and periglomerular fibrosis Glomeruli are not significantly involved except for late development of focal segmental sclerosis Calyceal system shows chronic inflammation Chronic interstitial nephritis Morphology varies depending upon etiologic agent Interstitial fibrosis and tubular atrophy are common Interstitial inflammatory infiltrates of variable degree composed of lymphocytes, plasma cells Lithium nephropathy: Tubular dilatation is characteristic with single cell lining and segmental glomerulosclerosis

Urate nephropathy: Urate crystals with birefringent needle-shaped appearance in tubular lumen &/or interstitium surrounded by foreign body giant cell reaction Chronic infections Renal tuberculosis Granulomatous inflammation with caseous necrosis Interstitial fibrosis and tubular atrophy Large coalescent granulomas may form large masses Xanthogranulomatous pyelonephritis Diffuse granulomatous inflammatory tubulointerstitial infiltrate with numerous foamy cells, lipid-laden macrophages, and occasional multinucleated giant cells Additional inflammatory cells include lymphocytes, plasma cells, and neutrophils Malakoplakia Nodules composed of clusters of macrophages with foamy eosinophilic cytoplasm (von Hanseman cells) Additional inflammatory infiltrate composed of lymphocytes and plasma cells Michaelis-Gutmann bodies inclusion (4-10 m) in macrophages or interstitium ADPKD Early stage cysts of variable size (0.5-5 cm) with normal intervening kidney parenchyma Late-stage cysts with fibrotic and atrophic intervening kidney parenchyma, global glomerulosclerosis, and glomerular cysts Cyst lining is usually single layer with flattenedappearing tubular cells Hypertensive nephropathy Arteries: Intimal fibrosis, elastic lamina reduplication, media hyperplasia Afferent arterioles show hyalinosis Glomerular ischemic changes Glomerular basement membrane (GBM) thickening and wrinkling Global glomerulosclerosis with solidified obsolescent glomeruli Segmental glomerulosclerosis Tubular atrophy Interstitial fibrosis Renal artery stenosis Proximal tubules with marked reduction in size, resulting in significant glomerular crowding Glomeruli are reduced in size with mild Bowman space dilatation Mild to moderate hyperplasia of juxtaglomerular apparatuses Fibromuscular dysplasia shows 3 patterns: Intimal fibroplasia, medial muscular dysplasia, and periarterial dysplasia Diabetic nephropathy Mesangial expansion, nodular in advanced stage GBM thickening Hyaline caps and capsular drop

Hyaline insudation/accumulation in arterioles (afferent and efferent)

ANCILLARY TESTS Histochemistry

Acid-fast bacilli useful for confirmation of renal tuberculosis

von Kossa stain useful to identify Michaelis-Gutmann bodies in malakoplakia

Elastic stain to evaluate renal artery stenosis caused by fibromuscular dysplasia

Immunofluorescence

Panel including IgG, IgA, IgM, C3, C1, light chains, albumin and fibrinogen is necessary in cases of glomerular diseases

Electron Microscopy Transmission

Necessary in cases of glomerular diseases for identification of electron-dense deposits and GBM abnormalities

REPORTING CRITERIA Final Report

Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC RENAL FAILURE

Should include

Etiology of CRF Whether CRF was cause of death or contributory factor Effects/complications in other organs of CRF

SELECTED REFERENCES 1.

Lopez-Giacoman S et al: Biomarkers in chronic kidney disease, from kidney function to kidney damage. World J Nephrol. 4(1):57-73, 2015 2. Buettner M et al: Nephropathy in illicit drug abusers: a postmortem analysis. Am J Kidney Dis. 63(6):945-53, 2014 3. D ez R et al: Renal AA amyloidosis in patients with type 2 diabetes mellitus. Nephron Extra. 4(2):119-26, 2014 4. Iwakiri T et al: Association between renal vasculature changes and generalized atherosclerosis: an autopsy survey. J Atheroscler Thromb. 21(2):99-107, 2014 5. Santoro A et al: Chronic renal disease and risk of cardiovascular morbidity-mortality. Kidney Blood Press Res. 39(2-3):142-6, 2014 6. Tomino Y: Pathogenesis and treatment of chronic kidney disease: a review of our recent basic and clinical data. Kidney Blood Press Res. 39(5):450-89, 2014 7. Tuttle KR et al: Diabetic kidney disease: a report from an ADA Consensus Conference. Am J Kidney Dis. 64(4):510-33, 2014 8. Zachariah D et al: Sudden cardiac death in end stage renal disease: unlocking the mystery. J Nephrol. Epub ahead of print, 2014 9. Zhao J et al: Assessment of renal fibrosis in chronic kidney disease using diffusion-weighted MRI. Clin Radiol. 69(11):1117-22, 2014 10. Roberts WC et al: Cardiac findings at necropsy in patients with chronic kidney disease maintained on chronic hemodialysis. Medicine (Baltimore). 91(3):165-78, 2012

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CHRONIC RENAL FAILURE

Gross and Microscopic Features (Left) In chronic pyelonephritis, kidney is reduced in size, with marked destruction of renal parenchyma & dilatation of calyces, forming cyst . Note abscess filled with necrotic debris . (Right) Posterior urethral valve is an obstructing membrane in the posterior male urethra as a result of abnormal in utero development. It is the most common cause of bladder outlet obstruction in male newborns, can cause hydroureter & hydronephrosis, and is a risk factor for chronic pyelonephritis.

(Left) This section of a case of chronic pyelonephritis shows tubular thyroidization, which is characterized by atrophic tubules with attenuated epithelium and luminal colloidlike hyaline casts . Patchy chronic inflammation is seen in the interstitium . (Right) In chronic pyelonephritis, tubulointerstitial inflammation containing lymphocytes, plasma cells, and mononuclear cells with associated geographic/jigsaw pattern of interstitial fibrosis and tubular atrophy are characteristic.

(Left) In urate nephropathy, there is accumulation of needle-like crystals , associated with an inflammatory infiltrate in the interstitium, characteristic of a gouty tophus. (Right) 2,8 dihydroxyadeninuria crystalline nephropathy, a rare autosomal recessive inherited disorder of purine metabolism, clinically varies from an asymptomatic state to recurrent nephrolithiasis, recurrent urinary tract infection, and CRF. Crystals are present in tubular lumina and are polarizable .

Gross and Microscopic Features (Left) Gross specimen from a case of miliary tuberculosis shows numerous small foci of caseous necrosis in the cortex and medulla. (Right) Granulomas with caseous necrosis are characteristic microscopic features of tuberculosis . Tuberculosis involving the kidney is most commonly seen in immunosuppressed patients with HIV infection or transplants. Fungal infections may also manifest with necrotizing granulomas. Special stains are necessary for identification of microorganisms.

(Left) Xanthogranulomatous pyelonephritis is a variant of chronic pyelonephritis, characterized by mass lesions with many foamy macrophages forming granulomas . Proteus mirabilis is the most common causative agent. (Right) At higher magnification in a case of xanthogranulomatous pyelonephritis, there is prominent foamy macrophage infiltration with scattered lymphocytes and plasma cells.

(Left) Malakoplakia is caused by chronic bacterial infection. Histologically, macrophages with foamy cytoplasm containing PAS-positive MichaelisGutmann bodies are seen. (Right) Megalocytic interstitial nephritis is closely related to malakoplakia and it is caused by chronic gramnegative bacterial infection. The lesion is characterized by interstitial infiltration of histiocytes with eosinophilic granular cytoplasm . In contrast to malakoplakia, there are no MichaelisGutmann bodies.

Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC RENAL FAILURE

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CHRONIC RENAL FAILURE

Gross and Microscopic Features (Left) Autosomal dominant polycystic kidney disease on gross examination shows replacement of the kidney parenchyma by multiple cysts with variable size, thin walls, and containing clear or hemorrhagic fluid. (Right) Autosomal dominant polycystic kidney disease on gross examination shows multiple cysts of variable size with thin walls and smooth-appearing internal surfaces. The pyelocalyceal system is distorted and dilated .

(Left) H&E section of a case of ADPKD demonstrates cysts walls lined by an attenuated layer of epithelial cells with scant parenchyma containing atrophic tubules and interstitial fibrosis . (Right) In ADPKD, other organs are frequently involved. In 15% of cases, aneurysms in the circle of Willis can be identified. They may rupture and be the cause of death with extensive subarachnoid hemorrhage .

(Left) Hypertensive nephrosclerosis initially affects arterioles and arteries, but with progression of the disease, the glomeruli are involved and develop global glomerulosclerosis . The arteriole appears thickened and with reduplication of elastic lamina . (Right) In hypertensive nephrosclerosis, the arterioles show thickening of the wall with deposits of hyaline material in subendothelial distribution that eventually becomes circumferential .

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Microscopic Features (Left) The large arteries in hypertensive nephrosclerosis show varying degrees of tunica media thickening and intimal fibrosis with reduplication of internal elastic lamina . (Right) Diabetic nephropathy is characterized by expansion of the mesangial matrix nodular formation. The nodules are of different size and involve the glomerular tuft irregularly. The nodules are composed mainly of matrix.

(Left) In the advanced phase of diabetic nephropathy, the mesangial matrix expansion often forms nodules known as KimmelstielWilson nodules. On silver stain, the matrix shows a lamellated appearance . There is hyaline deposition (insudation of plasma proteins) in afferent and efferent arterioles , and hyaline caps are also present . (Right) In amyloidosis, there is mesangial expansion with acellular amorphous eosinophilic material that is paler than the normal mesangial matrix.

(Left) The amyloid deposits in the mesangium show birefringent apple-green color under polarized light. This characteristic feature is useful for diagnosis. (Right) On ultrastructural examination, amyloid deposits show randomly arranged nonbranching fibrils with diameters varying from 0.8-1.2 m. These features are characteristic and allow differentiation from fibrillary or immunotactoid glomerulopathies where the deposits are larger.

Disease Process Approach to Autopsy: Other Common Hospital Death

CHRONIC RENAL FAILURE

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DEMENTIA AND NEURODEGENERATIVE DISEASE

Autopsy specimen of frontotemporal dementia shows striking atrophy of the frontal gyri with normalappearing parietal and occipital lobes. (From Osborn’s Brain.)

ETIOLOGY/PATHOGENESIS

CLINICAL ISSUES

Alzheimer Disease (AD)

Epidemiology

Most common neurodegenerative disease, incidence with age

Tauopathies

AD, Pick disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic grain disease

Multi-Infarct Dementia

Shared risk factors for atherosclerosis

Frontotemporal Dementias (FTD)

Pick disease, FTD with inclusions (positive for tdp-43, neurofilament, fused in sarcoma protein [FUS], p62, ubiquitin)

Amyotrophic Lateral Sclerosis (ALS) With Dementia

Spectrum from ALS only to ALS with frontotemporal dementia to pure frontotemporal dementia with ubiquitin positive inclusions

Synucleinopathies

Parkinson disease (PD), Lewy body dementia (LBD), multisystem atrophy (MSA)

Other Heritable Conditions

Huntington disease (HD), spinocerebellar ataxias, Friedrich ataxia, inherited amyloidoses

Other Acquired Conditions

Acquired-B12 deficiency, chronic traumatic encephalopathy, Wernicke-Korsakoff

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Coronal autopsy section from a patient with early Alzheimer disease shows enlarged lateral ventricles. The hippocampi appear mildly atrophic. (From Osborn’s Brain.)

Incidence

AD is most common neurodegenerative disease Not a normal part of aging but incidence with advancing age: Incidence 1/100 in 65-59 year olds Prevalence doubles with 5-year increments after age 70 Younger onset with inherited AD (mutations in amyloid precursor protein [APP], pre-senilin 1, pre-senilin 2; all autosomal dominant) Down syndrome (APP gene on chromosome 21) Multi-infarct dementia occurs with other risk factors for and manifestations of cardiovascular disease Note that patients with autosomal dominant inherited diseases with trinucleotide repeats (e.g., HD) may show earlier onset in successive generation PD also increases with increasing age but has earlyonset heritable forms in 10% of cases Heritable forms may be autosomal dominant or recessive

Presentation

AD: Insidious onset, disturbances in recent memory function, visuospatial disorders, behavioral change

Multi-infarct dementia: Stepwise deterioration FTD: Progressive aphasia, behavioral change, semantic dementia (language difficulties)

Movement disorders

PD: Tremor, rigidity, responsive to L-dopa LBD: Tremor, rigidity, not responsive to L-dopa, with visual hallucination HD: Chorea Corticobasilar degeneration: "Alien limb" Prion diseases: Rapidly progressive dementia (< 1 year), ataxia, myoclonus, sleep disturbances

Key Facts Clinical Issues

Common causes of death

Aspiration pneumonia, other infections, choking, or respiratory failure Other infections Pulmonary thromboembolism Falls due to extrapyramidal symptoms, weakness, orthostatic hypotension, and deconditioning from immobility Decreased nutritional intake, generalized deconditioning contribute to comorbidity

Macroscopic Pathology Routine sampling

Frontal, temporal, anterior cingulate, parietal (ink the precentral gyrus before sectioning), occipital cortex

Hippocampus, amygdala Caudate, putamen, globus pallidus, subthalamic nucleus Midbrain (with substantia nigra), pons (with locus ceruleus), medulla Cerebellar vermis, dentate Target to suspected disorder based on clinical signs and symptoms

Diagnostic Checklist

Alzheimer: Plaque frequency does not correlate well with clinical dementia, but tangle frequency and distribution does Parkinson: Most of the loss of pigmented neurons in pars compacta of substantia nigra occurs laterally and ventrally, whereas in normal aging, what loss there is occurs medially and dorsally

Laboratory Tests

Evidence of deep vein thrombosis (asymmetrical calf

(AD), huntingtin (HD) Autonomic testing: Impaired in PD, MSA Cerebrospinal fluid testing for prion disease (14-3-3 protein and tau)

Internal Examination

Prognosis

Brain Examination

Genetic testing: SNCA (synucleinopathies), PSEN1

Aspiration pneumonia, infections, respiratory failure are common causes of death Decreased nutritional intake, general deconditioning contribute to comorbidity Falls due to extrapyramidal symptoms, weakness, orthostatic hypotension, and deconditioning from immobility

IMAGE FINDINGS CT Findings AD

Enlarged ventricles May be lobar hemorrhage if associated amyloid angiopathy Cerebellar, pontine atrophy in MSA

MR Findings

AD: Hippocampal atrophy; frontal, temporal, and parietal atrophy

MSA: Atrophy of putamen, pons, ("hot cross bun" hyperintensity of pons), cerebellum

FTD: Severe focal frontal and temporal atrophy Creutzfeldt-Jakob disease (CJD): Hyperintensity of cortical ribbon, caudate, putamen

MACROSCOPIC FEATURES External Examination

Cachexia, features of Down syndrome, muscle atrophy indicating denervation, contractures

swelling), decubitus ulcers, fractures from recent falls, tongue biting from seizures

Aspiration pneumonia Atherosclerotic disease (multi-infarct dementia)

Disease Process Approach to Autopsy: Other Common Hospital Death

DEMENTIA AND NEURODEGENERATIVE DISEASE

Pattern of atrophy

AD: May be thinning of cortical ribbon, ventricular enlargement, diffuse atrophy HD: Flattening or concavity of caudate nucleus FTD: "Knife edge" atrophy of temporal lobes, frontal atrophy MSA: Atrophy of putamen, inferior olivary nuclei, pons, and cerebellum SCA: Pontine, olivary, or cerebellar atrophy CBD: Asymmetrical frontal and parietal atrophy, sometimes caudate and thalamus PSP: Atrophy of subthalamic nucleus, superior cerebellar peduncle ALS: May be atrophy of motor cortex (precentral gyrus); may be frontal and temporal atrophy if coexisting FTD Pigmentation Discoloration of putamen in MSA, globus pallidus in PSP and CBD Loss of pigment in substantia nigra in PD, LBD, MSA, PSP, CBD Pallor of locus ceruleus in PD, LBD, MSA, and AD Sampling Target to suspected disorder based on clinical signs and symptoms Cortex: Frontal, temporal, anterior cingulate, parietal, occipital Ink precentral gyrus (motor cortex) before serially sectioning Hippocampus, amygdala Basal ganglia and thalamus: Caudate, putamen, globus pallidus, subthalamic nucleus, mamillary bodies

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DEMENTIA AND NEURODEGENERATIVE DISEASE Brainstem: Midbrain (with substantia nigra), pons (with locus ceruleus), medulla Cerebellum: Vermis, dentate Cervical, thoracic, and lumbar cord (esp. in ALS, spinocerebellar ataxias, Friedrich ataxia, B12 deficiency)

MICROSCOPIC PATHOLOGY Histologic Features

Amyloid plaques, neurofibrillary tangles (AD) Neuronal inclusions

PD, LBD: Lewy bodies (alpha synuclein [+]) PSP, CBD: Balloon neurons ALS: Skein-like inclusions Glial inclusions MSA: Cytoplasmic in oligodendrocytes PSP: Tufted/"thorny" astrocytes CBD: Astrocytic plaques Spongiotic degeneration Prion disease: Throughout cortex, thalamus, &/or cerebellum AD, LBD: Superficial cortex only (in severe forms) Neuronal loss PD: Atrophy and loss in substantia nigra (midbrain)

ANCILLARY TESTS

Only neuritic plaques relevant to a diagnosis of AD; must be interpreted in context (patient age, signs and symptoms) Plaque frequency does not correlate well with clinical dementia severity, but tangle frequency and distribution does -amyloid plaques are extracellular; neurofibrillary tangles are intracellular PD Lewy bodies are never a normal finding in aging Loss of pigmented neurons in pars compacta of substantia nigra (lateral and ventral), whereas in normal aging, loss is medial and dorsal

REPORTING CRITERIA Cause of Death

Generally secondary effect of dementia rather than neurodegeneration alone Aspiration, sepsis, or other systemic findings

Clinicopathologic Correlation

AD diagnosis requires clinical history of dementia, and absence of another cause of dementia

Findings of AD frequently coexist with LBD Multiple vascular subcortical lesions are more suggestive of multiinfarct dementia than lacunar infarcts

Histochemistry

Congo red (or beta amyloid IHC)

Staining pattern Extracellular amyloid plaques of AD and prion disease Amyloid in media of vessels in amyloid angiopathies Silver stains: Bielschowsky, Gallyas, or Bodian Stain plaques and wide variety of inclusions with varying sensitivities

Immunohistochemistry

Ubiquitin: Highlights intraneuronal inclusions (e.g., SCA, Huntington, and ALS) -synuclein: Lewy bodies and Lewy neurits in neuronal processes, glial cytoplasmic inclusions in MSA Tau: Hyperphosphorylated tau seen in neurofibrillary tangles of AD, Pick bodies in Pick disease, inclusions of CBD, PSP

DIAGNOSTIC CHECKLIST Pathologic Interpretation Pearls Normal aging

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Both diffuse plaques and varying number of neuritic plaques (amyloid plaques with a core of dystrophic neurites) Hippocampal neurofibrillary tangles found in normal aging (but cortical tangles specific for dementia)

SELECTED REFERENCES 1.

2. 3. 4.

Cure S et al: Systematic literature review and meta-analysis of diagnostic test accuracy in Alzheimer’s disease and other dementia using autopsy as standard of truth. J Alzheimers Dis. 42(1):169-82, 2014 Bigio EH: Making the diagnosis of frontotemporal lobar degeneration. Arch Pathol Lab Med. 137(3):314-25, 2013 Jordan BD: The clinical spectrum of sport-related traumatic brain injury. Nat Rev Neurol. 9(4):222-30, 2013 Kojima G et al: Creutzfeldt-Jakob disease: a case report and differential diagnoses. Hawaii J Med Public Health. 72(4):136-9, 2013 Nelson PT et al: Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 71(5):362-81, 2012 Thompson PM et al: Pathologic lesions in neurodegenerative diseases. Prog Mol Biol Transl Sci. 107:1-40, 2012 Dickson D et al: Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. 2nd ed. New Jersey: Wiley-Blackwell, 2011 Fearnley JM et al: Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain. 114 ( Pt 5):2283-301, 1991

Gross and Microscopic Features (Left) Autopsy case of dementia with diffuse Lewy bodies shows mild, generalized volume loss without specific lobar predominance. Atrophy is manifest in part as widening of the sulci . (From Osborn’s Brain.) (Right) Axial section in the same case shows mildly enlarged ventricles with no other definite abnormalities identified. The occipital lobes appear normal. (From Osborn’s Brain.)

(Left) Autopsy of sporadic Creutzfeldt-Jakob disease shows marked atrophy of the caudate nuclei and anterior basal ganglia . The cerebral cortex is severely thinned, especially in the occipital lobes , where it is almost inapparent. (From Osborn’s Brain.) (Right) Autopsied sections compare normal midbrain (left) to one affected by Parkinson disease (right). Note midbrain volume loss in Parkinson disease and abnormal pallor of the substantia nigra . (From Osborn’s Brain.)

Disease Process Approach to Autopsy: Other Common Hospital Death

DEMENTIA AND NEURODEGENERATIVE DISEASE

(Left) These side-by-side photomicrographs are from patients with (right) and without (left) Parkinson disease. Pigmented cells can be seen in the substantia nigra area of the normal brain . (Right) These sideby-side photomicrographs at higher magnification show the substantia nigra neurons. The normal comparison shows retention of pigment , and the Parkinson patient shows pigmentary "incontinence."

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INDEX

Abdomen, postmortem physical exam, I(2):12 Abdominal aortic aneurysm, II(1):30-31 - differential diagnosis, II(1):31 Abrasions, examination, integumentary system, I(2):70 Abscesses - culture, I(2):85 - integumentary system, I(2):71 - kidney, I(2):50 Acanthosis nigricans, III(3):75 Acid fast bacteria, cytology, I(2):89 Acinus, I(2):26 Acquired aneurysms, II(2):156 Acquired conditions, III(4):100 Acquired immunodeficiency syndrome. See AIDS (acquired immunodeficiency syndrome). Acute antibody-mediated rejection, pancreas transplant, III(1):29 Acute cellular rejection (ACR), lung transplant, III(1):8 Acute coronary syndrome, II(1):4-7 Acute fibrinous and organizing pneumonia (AFOP), pulmonary edema vs., II(1):34 Acute hemolytic transfusion reaction, II(2):111 Acute kidney injury (AKI). See Acute renal failure. Acute liver failure, II(1):64-67, III(1):22 - chronic liver failure vs., III(4):89 - diagnostic checklist, II(1):66 - differential diagnosis, II(1):66 - histologic features, II(1):66 - microscopic and gross features, II(1):67 Acute myocardial infarction, II(1):4-7 - differential diagnosis, II(1):6 - gross and microscopic features, II(1):7 - tetrazolium chloride incubation for detection of, I(2):21 Acute pancreatitis, II(1):60 Acute renal failure, II(1):74-83 - differential diagnosis, II(1):77 - gross and microscopic features, II(1):79, 83 - variant microscopic features, II(1):78, 80-82 Acute T-cell-mediated cellular rejection, histologic features, lung transplant, III(1):10 Acute T-cell-mediated rejection - kidney transplant, III(1):12 - pancreas transplant, III(1):29 Acute tubular necrosis, acute renal failure vs., II(1):77 Addison disease, II(1):84-87 Adenocarcinoma - colon and rectum, I(2):37 - esophagus, I(2):35 - exocrine pancreas, I(2):44

- gastric, I(2):37 - small intestine, I(2):36 - stomach, I(2):36 Adenoma - adrenal cortical, II(1):89 - colon and rectum, I(2):37 - cortical, II(1):89 Adenomyoma, gallbladder, I(2):44 Adrenal agenesis, II(1):85 Adrenal cortical carcinoma, II(1):89 Adrenal cortical hyperplasia, II(1):89 Adrenal hemorrhage, II(1):84 Adrenal hypofunction, II(1):84-87 Adrenal insufficiency, II(1):84-87 - gross, radiologic, and microscopic features, II(1):87 Adrenal metastasis, II(1):85 Adrenals - common autopsy findings, I(2):55-56 - dissection techniques, I(2):54 - gross evaluation/sectioning, I(2):55 - histology, I(2):55 Adrenocortical excess, II(1):88-91 - gross features, II(1):90 - microscopic features, II(1):91 Adrenogenital syndrome, II(1):88 Adrenoleukodystrophy, II(1):85 AICD generators, external examination process, I(2):13 AIDS (acquired immunodeficiency syndrome), III(2):38-41 - gross and microscopic features, III(2):41 Alcoholic liver disease, III(4):86 Aldosteronism, II(1):88 Alexandria, I(1):2 Allograft thrombosis, pancreas transplant, III(1):29 Alpha-1-antitrypsin (A1AT) deficiency, III(4):86 Alveoli, I(2):26 Alzheimer disease (AD), III(4):100 American Heart Association Classification, II(1):8-9 AMR. See Antibody-mediated rejection (AMR). Amyloidosis, I(2):30 Amyotrophic lateral sclerosis (ALS), with dementia, III(4):100 Anaplastic large cell lymphoma, I(2):30 Anastomosis, II(2):115 - Roux-en-Y, II(2):142 Anastomotic complications, lung transplant, III(1):8 Aneurysms - acquired, II(2):156 - definition, II(2):132 - developmental, II(2):156 - dissecting, II(1):24-29 - thoracic aortic, repair, II(2):132-137 differential diagnosis, II(2):134 Angioimmunoblastic T-cell lymphoma, I(2):29

INDEX Angioma, cavernous, II(2):156 Angiomyolipomas, I(2):50 Anoxia, central nervous system, I(2):60 Antemortem interventions, external evidence, I(2):9 Antibody-mediated rejection (AMR) - heart transplant, III(1):2 - kidney transplant, III(1):12 - lung transplant, III(1):8, 10 Aorta, postmortem radiography and virtual autopsy, I(2):94 Aortic dissection, II(1):24-29 - extension and risk factors, II(1):28 - gross features, II(1):27 - operative intervention and microscopic features, II(1):29 Aortoduodenal fistula, II(1):45, 46 Aphthous ulcer, I(2):75 Appendicitis, I(2):37 Appendix, examination, I(2):37 Arrhythmias, endovascular ablation procedures, II(1):20 Arrhythmogenic cardiomyopathy, II(1):10 Arterial fibrointimal thickening (cv), Banff scoring categories, kidney transplant, III(1):15 Arteries - bronchial, I(2):24 - pulmonary, I(2):26 Arteriolar hyalinosis (ah), Banff scoring categories, kidney transplant, III(1):16 Arteriosclerosis, II(1):104 Arteriovenous malformation (AVM), II(2):156 Ascending infections, urosepsis, III(2):64 Ascites, I(2):16 - culture, I(2):85 - peritoneal cavity, I(2):17 Aspiration, histologic features, lung transplant, III(1):10 Asthma, COPD, III(4):80 Atelectasis, I(2):25 Atherosclerosis, II(1):104 Atrioventricular (AV) node, II(1):18, 19 Atrioventricular block, congenital, II(1):19 Atrophy - cortical, II(1):89 - splenic, I(2):30 Autoimmune adrenalitis, II(1):84 Autoimmune hepatitis, III(4):86 Autolysis - intestinal ischemia vs., II(1):54 - lower gastrointestinal hemorrhage vs., II(1):50 Autopsy - authorizing, I(3):100 - consent documents, I(3):101 - day following, I(3):108-109 - day of, I(3):108 - deceased donor, III(1):36-37 differential diagnosis, III(1):37 - evolution, I(1):5 - history, I(1):2-5 advances toward modern autopsy practice, I(1):2-4 ancient society, death remains, and medicine, I(1):2 challenges and alternatives, I(1):4 Europe, I(1):2-3 ii

notable, I(1):4 USA, I(1):3 - interdepartmental case conference presentations, I(3):109 - lung allograft pathology, III(1):11 - photography, I(3):109 - presenting findings, I(3):108-109 - requesting, I(3):100 - restricting, I(3):100 - virtual vs. traditional, I(2):95 Autopsy report, I(3):106-107 - final, I(3):106-107 - provisional, I(3):107 Autopsy safety, I(1):6-7 AVM. See Arteriovenous malformation (AVM).

Back, postmortem physical exam, I(2):13 Bacteria, cytology, I(2):89 Bacterial culture, techniques, I(2):85-86 Bacterial myocarditis, myocarditis vs., II(1):14 BALT. See Bronchial-associated lymphoid tissue (BALT). Bariatric surgery, II(2):146-149 - complications, II(2):147 - gross and microscopic features, II(2):149 - types, II(2):146 Barrett esophagus, I(2):35, 37 Basal cell carcinoma, I(2):70 BAV. See Bicuspid aortic valve (BAV). Bezoar, I(2):36 Bicuspid aortic valve (BAV), II(2):132 Biliary diseases, III(4):86 Biliary tree, dissection, I(2):34 Biliopancreatic diversion, II(2):146 Bilirubin, postmortem changes, I(2):82 Billroth I operation, II(2):142 Billroth II operation, II(2):142 Bioprosthetic valves, II(2):122 - catheter-deployed, II(2):122 complications, II(2):123 Bladder - dissection, I(2):49 - examination, I(2):50 Blood - collection of, I(2):83 - components, postmortem changes, I(2):82 - culture, I(2):85 - extrinsic, pulmonary hemorrhage vs., II(1):38 - peripheral, I(2):28 Blood-borne infections, urosepsis, III(2):64 Blood vessel hamartomas, II(2):156 Body cavities, I(2):16-19 - examination, I(2):50 - gross features, I(2):19 Body fluids, methods of collection, I(2):83 Boerhaave, Herman, I(1):4 Boerhaave syndrome, I(2):35 Bone marrow, I(2):28-29 - examination, I(2):33

INDEX Bone marrow transplant, III(1):32-35 - microscopic features, III(1):34-35 Brachial plexus, dissection techniques, I(2):66 Brain, I(2):60 - cutting, I(2):60-61, 64-65 - removal and prosection, I(2):63 Brain death, primary vs. secondary effects, deceased donor autopsy vs., III(1):37 Bronchi, I(2):25 Bronchial arterial bleeding, pulmonary hemorrhage vs., II(1):38 Bronchial arteries, I(2):24 Bronchial-associated lymphoid tissue (BALT), I(2):26 Bronchioles, I(2):26 Bronchitis, chronic, COPD, III(4):80 Bronchopneumonia, I(2):26, III(2):48-51 - differential diagnosis, III(2):50 - gross and microscopic features, III(2):51 Bruises, examination, integumentary system, I(2):70 Bullae, I(2):75 Burkitt lymphoma, I(2):29 Burns, examination, I(2):70

CABG. See Coronary artery bypass grafting. Cameron lesion, II(1):45, 46 Candida albicans, III(2):38, 40 Candida infection, esophagus, I(2):35 Candidiasis, oral, I(2):75 Capillary hemangioma, II(2):156 Carbohydrates, postmortem changes, I(2):82 Carcinoid syndrome, III(3):76 Carcinoma - adrenal cortical, II(1):89 - basal cell, I(2):70 - cortical, II(1):89 - cytology, I(2):89 - peritoneal cavity, I(2):18 - renal cell, I(2):50 Carcinomatosis, peritoneal cavity, I(2):18 Cardiac allograft vasculopathy (CAV), III(1):2 Cardiac arrest, unclear death certification, I(3):103 Cardiac conduction system, II(1):18-23 - gross and microscopic features, II(1):21-23 - histologic pitfalls, II(1):19 - major diseases affecting, II(1):19 Cardiomyopathy, II(1):8-11 - diagnostic checklist, II(1):10 - dilated, idiopathic, I(2):21 - gross and microscopic features, II(1):11 Cardiopulmonary resuscitation (CPR), tension pneumothorax vs., II(1):42 Cardiovascular devices, I(2):79 Cardiovascular system, I(2):20-23 - diseases at autopsy, I(2):21 - examination, I(2):50 - gross features, I(2):22-23 - postmortem radiography and virtual autopsy, I(2):94 - radiographic analysis, I(2):96

Caries, I(2):74 Catheter-deployed bioprosthetic valves, II(2):122 - complications, II(2):123 CAV. See Cardiac allograft vasculopathy (CAV). Cavernous angioma, II(2):156 Cavities, I(2):74 CBD. See Common bile duct (CBD). C4d score in PTC (C4d), Banff scoring categories, kidney transplant, III(1):16 Celiac disease, I(2):36 Cellular rejection (CR), heart transplant, III(1):2 Central lines, external examination process, I(2):13 Central nervous system (CNS), I(2):60-65 - postmortem radiography and virtual autopsy, I(2):95 - tumors, II(2):150-155 familial, II(2):150 gross features, II(2):152-153 metastatic, II(2):150 microscopic features, II(2):153-155 post radiation, II(2):150 sporadic, II(2):150 Cerebellar degeneration, III(3):75 Cerebral aneurysm and vascular malformation, II(2):156161 - gross and angiographic features, II(2):159-160 - microscopic features, II(2):160-161 Cerebrospinal fluid, culture, I(2):85 Cervical plexus, dissection techniques, I(2):66 Cheilitis, angular, I(2):74 Chemical risk reduction, I(1):6-7 Chemistry, I(2):82-83 Chest, postmortem physical exam, I(2):12 Chest pain, acute myocardial infarction vs., II(1):6 Chest tubes, external examination process, I(2):13 Cholangiocarcinoma, I(2):44 Cholecystitis - acute, I(2):44 - chronic, I(2):44 Choledocholithiasis, I(2):44 Cholelithiasis, I(2):44 Cholesterolosis, I(2):44 Chronic bronchitis, COPD, III(4):80 Chronic cellular rejection, kidney transplant, III(1):12 Chronic kidney disease (CKD), III(4):92-99 Chronic liver failure, III(1):22, III(4):86-91 - causes, III(4):90 - complications, III(4):91 - differential diagnosis, III(4):89 Chronic lung allograft dysfunction (CLAD), lung transplant, III(1):8 Chronic lymphocytic lymphoma, I(2):29 Chronic obstructive pulmonary disease. See COPD (chronic obstructive pulmonary disease). Chronic rejection - histologic features, lung transplant, III(1):10 - pancreas transplant, III(1):29 Chronic renal failure, III(4):92-99 - gross features, III(4):96-98 - microscopic features, III(4):96-99 Chronic viral hepatitis infection, III(4):86 Chylothorax, pleural cavity, I(2):17 iii

INDEX Chylous ascites, peritoneal cavity, I(2):18 Cirrhosis - acute liver failure vs., II(1):66 - liver, I(2):44 Cisternal puncture, I(2):85 Clindamycin-associated colitis, III(2):56-59 Clostridium difficile-associated disease (CDAD), III(2):56-59 Clostridium difficile colitis, III(2):58 - severe, III(2):59 Clostridium difficile enterocolitis, III(2):56-59 - differential diagnosis, III(2):57 CMV. See Cytomegalovirus (CMV). CNS. See Central nervous system (CNS). Coccidioides immitis, III(2):38, 40 Coccygeal plexus, dissection techniques, I(2):66 Colitis - clindamycin-associated, III(2):56-59 - Clostridium difficile, III(2):58 severe, III(2):59 - ischemic, II(1):52, III(2):58 - pseudomembranous, Clostridium difficile enterocolitis vs., III(2):57 Colon, I(2):41 - examination, I(2):36-37 Common bile duct (CBD), I(2):42 Communication, consent process and legal considerations, I(3):100 Community-acquired pneumonia (CAP), III(2):48 Compartment syndromes, life-threatening, acute, I(2):16 Congenital adrenal hypoplasia, II(1):85 Connective tissue disorders, I(2):71 - inherited or acquired, II(1):24 Consent process - authorization, I(3):100 - disposition of remains, I(3):100 - and legal considerations, I(3):100-101 - limitations, I(3):100 - risk mitigation, I(3):101 Contaminants, isolation, I(2):86 Continuous flow pump devices, II(2):130 COPD (chronic obstructive pulmonary disease), III(4):7881 - gross and microscopic images, III(4):81 Coronary arteries, postmortem radiography and virtual autopsy, I(2):94 Coronary artery atherosclerosis, risk factors, II(1):4 Coronary artery bypass grafting (CABG), II(2):114-117 - gross features, II(2):116 - microscopic features, II(2):117 Coronary artery disease, III(2):38 Coronary artery stenting, II(2):118-121 - complications, II(2):118 - indications, II(2):118 - microscopic features, II(2):120-121 Coronary dissection, spontaneous, II(1):70 Coronary grafts, postmortem radiography and virtual autopsy, I(2):94 Coronary syndrome, acute, II(1):4-7 Cortical atrophy, II(1):89 Cortical carcinoma, II(1):89 Cortical hyperplasia, II(1):89 iv

Creutzfeldt-Jakob disease (CJD), high-risk autopsy, I(1):7 Crohn disease, I(2):36, 37 Cryptococcus neoformans, III(2):38, 40 Cryptosporidium, III(2):40 Cultures, postmortem, I(2):84 - techniques, I(2):85-86 Cushing syndrome, III(3):75 Cystic neoplasms, exocrine pancreas, I(2):44 Cystic tumor, of AV node, II(1):19 Cystitis, urosepsis, III(2):64 Cysts, peritoneal, I(2):18 Cytology, I(2):88-93 - advantages of autopsy, I(2):89 - disadvantages of autopsy, I(2):89 - limited cases, I(2):93 - microscopic features, I(2):92 - techniques, I(2):88-89 Cytomegalovirus (CMV), III(2):38, 40 - esophagus, I(2):35 Cytomegalovirus (CMV) myocarditis, myocarditis vs., II(1):14

De Humani Corporis Fabrica, I(1):3 de novo Glomerular disease, kidney transplant, III(1):12 Death - brain, deceased donor autopsy vs., III(1):37 - cause, I(3):102 - due to paraneoplastic effect, III(3):74-77 gross and histologic features, III(3):77 - manner, I(3):102-103 - neoplasia-associated, III(3):68-73 general features of malignancy, III(3):72 infectious and paraneoplastic complications of malignancy, III(3):71 therapeutic complications, III(3):73 - sudden, cardiac, I(2):21 Death certificate (DC), I(3):102-105 - amending, I(3):103 - data, I(3):103 - physician responsibility, I(3):102-103 - unclear, I(3):103 Death statements, cause, I(3):104-105 Debilitation, central nervous system, I(2):60 Deceased donor autopsy, III(1):36-37 - differential diagnosis, III(1):37 Decomposition, postmortem, I(2):13 Deformities, central nervous system, I(2):60 Dementia - amyotrophic lateral sclerosis with, III(4):100 - multi-infarct, III(4):100 - and neurodegenerative disease, III(4):100-103 diagnostic checklist, III(4):102 gross and microscopic features, III(4):103 Dermatitis, I(2):71 Dermatologic diseases, at autopsy, I(2):71 Dermatomyositis, III(3):74 Developmental aneurysms, II(2):156 Diabetes mellitus, body fluid analysis, I(2):83

INDEX Diamond saw microtome, II(2):119 Dieulafoy lesion, II(1):45, 46 Diffuse alveolar damage, I(2):26 - early, II(1):35 Diffuse alveolar hemorrhage (DAH), II(1):36 - gross and microscopic appearance, II(1):39 Diffuse large cell lymphoma, I(2):29 Dilated cardiomyopathy, III(2):38 Dissecting hematoma, II(1):24-29 Disseminated intravascular coagulation, I(2):71 Diverticular disease, I(2):36 Documentation, consent process and legal considerations, I(3):100 Dolichoectasia, II(2):158 Drug/toxin induced acute liver failure, II(1):64 Drug/toxin-induced injury, chronic liver failure, III(4):86 "Dry mouth," I(2):75 Dural arteriovenous fistula or shunt, II(2):156

Eclampsia, II(1):69 Effusions - body cavities, I(2):16 - culture, I(2):85 Ehlers-Danlos syndrome, I(2):71 - vascular, II(1):25 Electrical shock risk reduction, I(1):6 Electrolytes, postmortem changes, I(2):82 Embalming, I(3):101 Embolic infarction, II(1):104 Embolism, amniotic fluid, II(1):69 Emphysema, COPD, III(4):80 Empyema, pleural cavity, I(2):17 Endocarditis - infective, II(2):124, III(2):52-55 differential diagnosis, III(2):53 gross features, III(2):54 microscopic features, III(2):55 prosthetic valve failure, II(2):123 - nonbacterial thrombotic, infective endocarditis vs., III(2):53 Endocrine disease, external examination clues to, I(2):56 Endocrine organs, in situ, excised, I(2):57 Endocrine system, I(2):54-59 - common autopsy findings, I(2):55-56, 59 - dissection techniques, I(2):54 - gross evaluation/sectioning, I(2):55 - histology, I(2):55, 58 Endometriosis, peritoneal cavity, I(2):18 Endotracheal tube (ETT), external examination process, I(2):13 Enterococcus, III(2):67 Enterocolitis, Clostridium difficile, III(2):56-59 - differential diagnosis, III(2):57 Enzyme-linked immunoassays, I(2):86 Enzymes, postmortem changes, I(2):82 Eosinophilia, III(3):76 Eosinophilic esophagitis, I(2):35, 37 Eosinophilic myocarditis, II(1):14

Ependymoma, II(2):151 Erythema multiforme, I(2):71 Erythrocytosis, III(3):76 Erythroplakia, I(2):74 Esophageal varices, I(2):35, II(1):44, 45, 46 Esophagectomy, II(2):142-145 - gross and microscopic findings, II(2):145 - indications, II(2):142 Esophagitis, reflux, I(2):35, 37 Esophagus, I(2):39 - examination, I(2):35 Europe, in Middle Ages, I(1):2-3 Exfoliative cytology, I(2):88 External examination, I(2):12-15 - process, I(2):12-13 Extrahepatic bile ducts, I(2):42, 43 - frequent autopsy findings, I(2):44 - specimen handling, I(2):43 Extremities, postmortem physical exam, I(2):12-13 Extrinsic blood, pulmonary hemorrhage vs., II(1):38 Exudates, body cavities, I(2):16

Face, postmortem physical exam, I(2):12 Felty syndrome, I(2):30 Female genital tract, I(2):48 Femoral venipuncture, I(2):85 Fetal CNS, I(2):61 Fevers, viral hemorrhagic, III(2):60, 62 Final autopsy report, I(3):106-107 Fine needle aspiration (FNA), I(2):88, 90 Fixed dissected organs, presentation, I(3):108-109 FNA. See Fine needle aspiration (FNA). Focal cortical dysplasia/tubers, II(1):94 Foix-Alajouanine syndrome, II(2):156 Foley catheter, external examination process, I(2):13 Follicular lymphoma, I(2):29 Foreign material, radiographic analysis, I(2):98 Frontotemporal dementias (FTD), III(4):100 FTD. See Frontotemporal dementias (FTD). Funeral homes, coordination with, I(3):101 Fungal culture, techniques, I(2):85-86 Fungi, cytology, I(2):89

Galen, I(1):2 Gallbladder, I(2):42, 43 - frequent autopsy findings, I(2):44 - specimen handling, I(2):43 GALT. See Gut-associated lymphoid tissue (GALT). Gastrectomy, II(2):142-145 - gross and microscopic findings, II(2):145 - indications, II(2):142 Gastric antral vascular ectasia, II(1):45, 46 Gastric banding, II(2):146 Gastric gland hyperplasia, I(2):36 Gastric polyps, I(2):36 v

INDEX Gastritis, I(2):35-36 Gastroduodenostomy, II(2):142 Gastrointestinal devices, I(2):79 Gastrointestinal (GI) tract - dissection, I(2):34-35 - removal, I(2):38 Gastrointestinal segment, inflation, I(2):35 Gastrointestinal stromal tumor (GIST), I(2):36, 37 Gastrointestinal system, I(2):34-41 Gastrojejunostomy, II(2):142 Gastropathy, hypertrophic, I(2):36 Gastrostomy tube, external examination process, I(2):13 Gaucher disease, I(2):30 Genetic syndromes, integumentary system, I(2):71 Genital tract, I(2):53 Genitalia, postmortem physical exam, I(2):13 Genitourinary devices, I(2):79 Genitourinary system, I(2):48-53 - dissection, I(2):51 - postmortem radiography and virtual autopsy, I(2):95 Germ cell tumors, testes, I(2):50 Giant cell myocarditis, II(1):14 - myocarditis vs., II(1):14 Gingival hyperplasia, I(2):75 Glioma, II(2):151 Glomerular diseases, III(4):92 Glomerulitis (g), Banff scoring categories, kidney transplant, III(1):15 Glomerulopathy, transplant (cg), Banff scoring categories, kidney transplant, III(1):15 Glossitis, I(2):75 Glycogen storage disorders, I(2):30 Graft-versus-host disease (GVHD), III(1):32, III(3):68 - grading, III(1):33 Granulomas, lymph nodes, I(2):29 Grinding, II(2):119 Gross consolidation, processes that mimic, bronchopneumonia vs., III(2):50 Gut-associated lymphoid tissue (GALT), I(2):28 Gynecologic tract - dissection, I(2):49 - examination, I(2):50

Hairy cell leukemia, I(2):29 Hamartoma, blood vessel, II(2):156 Hazard, definition, I(1):6 Head and neck, postmortem physical exam, I(2):12 Health care-associated pneumonia, III(2):48 Heart attack, II(1):4-7 Heart blood, culture, I(2):85 Heart disease, ischemic, I(2):21 Heart tissue, fresh, vital staining, II(1):6 Heart transplant, III(1):2-7 - artifacts confused with acute rejection, III(1):7 - microscopic features, III(1):5-6 Hemangioma, capillary, II(2):156 Hematobilia, II(1):45, 46 Hematolymphoid tissue, I(2):28 vi

Hematopoietic stem cell transplantation (HSCT), III(1):3235 Hematopoietic system, I(2):28-33 - dissection, I(2):28-29 - gross and microscopic features, I(2):32 Hematoxylin and eosin stain, I(2):89 Hemochromatosis, III(4):86 Hemopericardium, pericardial cavity, I(2):17 Hemoperitoneum, peritoneal cavity, I(2):18 Hemorrhage, II(1):104 - hepatic, II(1):56-59 gross and microscopic features, II(1):59 - lower gastrointestinal, II(1):48-51 differential diagnosis, II(1):50 gross and microscopic features, II(1):51 - in pancreatitis, II(1):60 - subarachnoid, II(1):100-103 gross and microscopic features, II(1):102-103 nontraumatic, II(1):100 radiologic features, II(1):103 - subdural, II(1):96-99 acute, II(1):97 chronic, II(1):97 diagnostic checklist, II(1):97 gross and microscopic features, II(1):98-99 subacute, II(1):97 - upper gastrointestinal, II(1):44-47 gross and microscopic features, II(1):47 Hemorrhagic infarct, II(1):5 Hemorrhagic pancreatitis, II(1):60-63 - organ changes, II(1):63 - pancreatic and peripancreatic findings, II(1):62 Hemosuccus pancreaticus, II(1):46 Hemothorax, pleural cavity, I(2):17 Hepatic cysts, I(2):50 Hepatic hemorrhage, II(1):56-59 - gross and microscopic features, II(1):59 Hepatitis - acute, liver, III(2):61 - autoimmune, II(1):64 - chronic, liver, III(2):61 - viral, II(1):64, III(2):60-63 microscopic findings, III(2):63 nonhepatotropic, III(2):62 Hepatitis virus, high-risk autopsy, I(1):7 Hepatobiliary devices, I(2):79 Hepatobiliary system, I(2):42-47 - clinical correlates, I(2):43 - frequent autopsy findings, I(2):43-44, 47 - histology, I(2):46 - postmortem radiography and virtual autopsy, I(2):95 - in situ and excised organs, I(2):45 - specimen handling, I(2):42-43 Hepatotropic viruses, III(2):60, 62 Heritable conditions, III(4):100 Hernias - peritoneal cavity, I(2):18 - small intestine, I(2):36 Herpes, esophagus, I(2):35 Herpes simplex virus (HSV), III(2):38, 40

INDEX High-risk autopsy - definition, I(1):6 - examples, I(1):7 Hilar lymph nodes, I(2):24 Hippocrates, I(1):2 His bundle, II(1):18, 19 Histology, nonculture methods, I(2):86 Histoplasma, III(2):38 Histoplasma capsulatum, III(2):38, 40 HIV (human immunodeficiency virus), III(2):38-41 - gross and microscopic features, III(2):41 - high-risk autopsy, I(1):7 Hodgkin lymphoma, I(2):30 - subtypes, I(2):31 Hormones, postmortem changes, I(2):82 Horseshoe kidney, I(2):50 Hospital-acquired pneumonia, III(2):48 Hospital autopsy, decline, I(1):3-4 Human immunodeficiency virus. See HIV (human immunodeficiency virus). Human leukocyte antigen (HLA), III(1):2 Human Tissue Act of 1961, I(3):101 Hydronephrosis, I(2):50 Hydroureter, I(2):50 Hyperacute rejection, pancreas transplant, III(1):29 Hypercalcemia, III(3):75 Hypercortisolism, II(1):88 Hyperinflation, I(2):25 Hyperplasia - adrenal cortical, II(1):89 - cortical, II(1):89 - prostate, I(2):50 Hypersensitivity myocarditis, myocarditis vs., II(1):14 Hypertension, II(1):24 - portal, spleen, I(2):30 Hypertensive nephrosclerosis, I(2):50 Hypertrophic cardiomyopathy, II(1):9-10 Hypertrophic osteoarthropathy, III(3):75 Hypoglycemia, III(3):75 Hypoplasia, I(2):25 Hypoxic-ischemic encephalopathy, II(1):94

Iatrogenic injury, II(2):110-113 Iatrogenically inserted devices, radiographic examination, I(2):97 Identification, and consent, I(2):12 Idiopathic dilated cardiomyopathy, I(2):21, II(1):9 IgG4-related disease, abdominal aortic aneurysm vs., II(1):31 Impression, I(2):88 Incised wounds, examination, I(2):70 Infarction, II(1):104 - acute myocardial, tetrazolium chloride incubation for detection of, I(2):21 - embolic, II(1):104 - splenic, I(2):30 Infection - histologic features, lung transplant, III(1):10

- lung transplant, III(1):8 - medical devices, I(2):79, 80 - neoplasia-associated death, III(3):68 Infection risk reduction, I(1):7 Infectious agents - cytology, I(2):89 - lymph nodes, I(2):29 - urosepsis, III(2):64 Infectious complications, bone marrow transplant, III(1):32 Infective endocarditis, II(2):124, III(2):52-55 - differential diagnosis, III(2):53 - gross features, III(2):54 - microscopic features, III(2):55 - prosthetic valve failure, II(2):123 Inflammatory aortic aneurysm, abdominal aortic aneurysm vs., II(1):31 Inflammatory bowel disease (IBD), I(2):36, 37 Injuries, examination, integumentary system, I(2):70 Inspection, postmortem, I(2):12-13 Integumentary system, I(2):70-73 - clinical features, I(2):72 - dermatologic diseases at autopsy, I(2):71 - microscopic features, I(2):73 - specimen handling, I(2):71 Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), II(2):128 Interstitial fibrosis (ci), Banff scoring categories, kidney transplant, III(1):15 Interstitial inflammation (i), Banff scoring categories, kidney transplant, III(1):15 Intestinal ischemia, II(1):52-55 - differential diagnosis, II(1):54 - gross and microscopic features, II(1):55 Intrapulmonary lymph nodes, I(2):24 Ischemia, gastrointestinal system, I(2):36-37 Ischemic colitis, III(2):58 Ischemic heart disease, I(2):21 Ischemic injury, kidney, I(2):50 Ivor Lewis esophagogastrectomy, II(2):142

J Joint effusions, culture, I(2):85

Keratosis - actinic, I(2):70 - seborrheic, I(2):70 Kidney - dissection, I(2):49 - examination, I(2):50 Kidney allograft, III(1):12-21 Kidney transplant, III(1):12-21 - gross features, III(1):19 - microscopic features, III(1):17-21 "Klatskin tumor," I(2):44 vii

INDEX

Lacerations - examination, integumentary system, I(2):70 - splenic, I(2):30 Lambert-Eaton myasthenia, III(3):75 Laparoscopic sleeve gastrectomy, II(2):146 Left ventricle dilatation, II(1):9 Left ventricular hypertrophy, II(1):9 Leiomyomas, colon and rectum, I(2):37 Leishmaniasis, visceral, I(2):30 Lenègre disease, II(1):20 Leser-Trélat sign, III(3):77 Lesions - cytologic evaluation, I(2):89 - examination, I(2):70 Leukemia - acute, I(2):31 - adult T-cell, I(2):29 - bone marrow, I(2):30 - hairy cell, I(2):29 - myelogenous, acute, I(2):31 Leukoplakia, I(2):74 Limb musculature, central nervous system, I(2):60 Limbic encephalitis, III(3):75 Lipids, postmortem changes, I(2):82 Liver, I(2):42, 43 - COPD, III(4):80 - frequent autopsy findings, I(2):43-44 - malignant infiltration, II(1):64 Liver failure - acute, II(1):64-67 diagnostic checklist, II(1):66 differential diagnosis, II(1):66 histologic features, II(1):66 microscopic and gross features, II(1):67 - body fluid analysis, I(2):83 - chronic, III(4):86-91 acute liver failure vs., II(1):66 causes of, III(4):90 complications of, III(4):91 differential diagnosis, III(4):89 Liver transplant, III(1):22-27 - diagnostic checklist, III(1):24 - gross and microscopic findings after, III(1):25-27 Livor, postmortem, I(2):13 Loeys-Dietz syndrome, II(1):25 Loose bodies, peritoneal cavity, I(2):18 Lower gastrointestinal bleed (LGIB), II(1):48-51 Lower gastrointestinal (GI) tract, I(2):34 Lumbar plexus, dissection techniques, I(2):66 Lung dissection technique, I(2):27 Lung transplant, III(1):8-11 Lungs, examination, I(2):50 Lymph nodes, I(2):24, 28 Lymphadenitis, I(2):29 Lymphocytic myocarditis, II(1):13 Lymphoid hyperplasia, I(2):30 viii

Lymphoid tissue - bronchial-associated, I(2):26 - gut-associated, I(2):28 Lymphoma - adult T-cell, I(2):29 - angioimmunoblastic T-cell, I(2):29 - cytology, I(2):89 - follicular, I(2):29 - gastrointestinal system, I(2):36 - large cell anaplastic, I(2):30 diffuse, I(2):29 - lymphoblastic, acute, I(2):29 - lymphocytic, chronic, I(2):29 - lymphoplasmacytic, I(2):29 - mantle cell, I(2):29 - marginal zone, splenic, I(2):30 - testes, I(2):50 Lymphoplasmacytic lymphoma, I(2):29

Macrophages, intraalveolar, I(2):26 Malaria, I(2):31 Male genital tract, I(2):48 Male urogenital tract, dissection, I(2):49 Malignancy, pulmonary hemorrhage vs., II(1):38 Malignant tumors - exocrine pancreas, I(2):44 - gynecologic tract, I(2):50 Mallory-Weiss tear, I(2):35, II(1):44-45, 46 Mantle cell lymphoma, I(2):29 Marantic endocarditis, III(3):76 Marfan syndrome, II(1):25 Marginal zone lymphoma, splenic, I(2):30 Maternal mortality, II(1):68 Mechanical prosthetic valves, II(2):122 Mechanical risk reduction, I(1):6 Meckel diverticulum, I(2):36 Mediastinal lymph nodes, I(2):24 Medical devices, I(2):78-81 - common, I(2):79 - complications, I(2):81 - examination approach, I(2):78-79 - infections, I(2):80 - photography of, I(2):79 - radiography of, I(2):79 - reporting considerations, I(2):79 Medical intervention, I(2):8-11 - external examination, I(2):10-11 - external examination process, I(2):13 Megacolon, I(2):37 Melanoma, I(2):71 - cytology, I(2):89 Melanosis cutis, III(3):75, 77 Menetrier disease, I(2):36 Meningioma, II(2):151 Mesangial matrix increase (mm), Banff scoring categories, kidney transplant, III(1):16

INDEX Mesenteric ischemia - acute, II(1):52 - chronic, II(1):52 Mesothelial cysts, peritoneal cavity, I(2):18 Mesothelioma - peritoneal cavity, I(2):18 - pleural cavity, I(2):17 Mesothelium, body cavity, I(2):18 Metabolic diseases, II(1):64, III(4):86, 92 - liver, III(1):22 Metastasis - adrenal, II(1):85 - hematopoietic system, I(2):30 Metastatic disease, full-body imaging, I(2):95 Metastatic tumors, II(2):151 Microbiologic testing, postmortem, indications, I(2):84 Microbiology, I(2):84-87 - gross and microscopic features, I(2):87 - interpretation of testing results, I(2):86 - nonculture methods, I(2):86 - techniques for bacterial, fungal, and viral cultures, I(2):85-86 Migratory thrombophlebitis, III(3):69, 76 Mismatched perfusion, II(1):4 Mixed myocarditis, II(1):13 Morbid obesity, II(2):146 Morgagni, Giovanni Battista, I(1):3, 5 Multi-infarct dementia, III(4):100 Multi-organ failure, III(2):42-47 Multiple myeloma, I(2):30, 31 Multiple organ dysfunction syndrome (MODS), III(2):42 Multiple systems organ failure, III(2):42-47 Musculoskeletal devices, I(2):79 Myasthenia gravis, III(3):75, 77 Mycobacterium tuberculosis - blood-borne infections, III(2):64 - high-risk autopsy, I(1):7 Mycosis fungoides, I(2):29 Myeloproliferative disorders - marrow, I(2):31 - spleen, I(2):30 Myocardial infarction, acute, II(1):4-7 - differential diagnosis, II(1):6 - gross and microscopic features, II(1):7 - tetrazolium chloride incubation for detection of, I(2):21 Myocardial ischemia, II(1):4-7 Myocardial recovery, II(2):128 Myocarditis, II(1):12-17, 19 - diagnostic checklist, II(1):14 - differential diagnosis, II(1):14 - microscopic features, II(1):15-17 - MR findings, II(1):15 Myocyte hypertrophy, II(1):9

NAFLD. See Nonalcoholic fatty liver disease (NAFLD). Nasogastric tube, external examination process, I(2):13 NBTE. See Nonbacterial thrombotic endocarditis (NBTE). Neck, postmortem physical exam, I(2):12

Necrolytic migratory erythema, III(3):75 Necrosis, acute esophageal, I(2):35 Neoplasia-associated death, III(3):68-73 - general features of malignancy, III(3):72 - infectious and paraneoplastic complications of malignancy, III(3):71 - therapeutic complications, III(3):73 Neoplasms, liver, III(1):22 Nephrolithiasis, I(2):50 Nephrosclerosis, hypertensive, I(2):50 Neurodegenerative disease, I(2):61 - dementia and, III(4):100-103 Neuroendocrine tumors, gastrointestinal system, I(2):36, 37 Neurofibromatosis type 1 (NF1), I(2):67 Neurofibromatosis type 2 (NF2), I(2):67 Neurologic devices, I(2):79 Neuropathy, disease/histologic findings of, I(2):67 Nitrogen compounds, postmortem changes, I(2):82 Non-Hodgkin lymphoma, I(2):29, 31 Nonalcoholic fatty liver disease (NAFLD), III(4):86 Nonatherosclerotic coronary disease, II(1):4 Nonbacterial thrombotic endocarditis (NBTE), III(3):69 - infective endocarditis vs., III(2):53 Nonhepatotropic viral hepatitis, liver, III(2):62 Nose, postmortem physical exam, I(2):12 Nucleic acid testing, I(2):86

Obesity, morbid, II(2):146 Opsoclonus-myoclonus, III(3):75 Oral cavity, I(2):74-77 - clinical features, I(2):76 - examination, I(2):75 - gross features, I(2):77 - microscopic features, I(2):76-77 - postmortem physical exam, I(2):12 - primary disease, I(2):74 - radiographic features, I(2):77 - specimen handling, I(2):75 - systemic disease manifestations, I(2):74-75 Oral thrush, I(2):75 Organ, procurement, I(2):9 Organ failure, multisystem, unclear death certification, I(3):103 Organ retention, consent process and legal considerations, I(3):100 Outflow obstruction, pulmonary hemorrhage vs., II(1):38

Pacer, external examination process, I(2):13 Pallor, I(2):30 Palpation, postmortem, I(2):12-13 Pancreas - dissection, I(2):34-35 - endocrine common autopsy findings, I(2):56 ix

INDEX dissection techniques, I(2):54 gross evaluation/sectioning, I(2):55 histology, I(2):55 - exocrine, I(2):42, 43 frequent autopsy findings, I(2):44 specimen handling, I(2):43 Pancreas allograft, III(1):28-31 - rejection, Banff schema for grading, III(1):30 Pancreas resection, II(2):138-141 - complications, II(2):139 - diagnostic checklist, II(2):140 - graphic, gross, and microscopic features, II(2):141 - indications, II(2):138 Pancreas transplant, III(1):28-31 - microscopic features, III(1):31 Pancreatectomy, II(2):138 Pancreatitis, III(1):29 - acute, I(2):44, II(1):60 - chronic, I(2):44 - hemorrhagic, II(1):60-63 organ changes, II(1):63 pancreatic and peripancreatic findings, II(1):62 Pannus formation, prosthetic valve failure, II(2):123 Papanicolaou stain, I(2):88 Paraneoplastic effect, death due to, III(3):74-77 - gross and histologic features, III(3):77 Paraneoplastic syndromes, III(3):68, 74 Paraprotein-associated diseases, III(4):92 Paraprotein-related renal disease, I(2):30 Parathyroid gland - common autopsy findings, I(2):55 - dissection techniques, I(2):54 - gross evaluation/sectioning, I(2):55 - histology, I(2):55 Paravalvular leak, prosthetic valve failure, II(2):122 Paris school, I(1):3 Pathogen, definition, I(1):6 Peliosis hepatis, II(1):57 Pelvis, examination, I(2):50 Peptic ulcer disease (PUD), I(2):36, II(1):44, 45, 46 Pericardial cavity, I(2):16, 17 Pericarditis, pericardial cavity, I(2):17 Periodontitis, I(2):74 Peripartum cardiomyopathy, II(1):70 Peripheral blood, I(2):28, 31 Peripheral nervous system, I(2):66-69 - autopsy indications, I(2):67 - dissection techniques, I(2):66 - gross evaluation/sectioning, I(2):66-67 - gross features, I(2):69 - microscopic features, I(2):68-69 Peritoneal cavity, I(2):16, 17-18 Peritonitis, peritoneal cavity, I(2):17 Peritubular capillary inflammation (ptc), Banff scoring categories, kidney transplant, III(1):16 Personal protective equipment (PPE), I(1):7 Peyer patches, hyperplastic, I(2):30-31 Pharyngitis, I(2):75 Photography, of devices, I(2):79 Piercings, examination, I(2):70 x

Pituitary gland - common autopsy findings, I(2):56 - dissection techniques, I(2):54 - gross evaluation/sectioning, I(2):55 - histology, I(2):55 Placenta accreta, II(1):69 Plaques, pleural cavity, I(2):17 Plasmacytomas, I(2):30 Plastic resin embedding, II(2):119 Pleural cavities, I(2):16, 17 Pleural effusions, culture, I(2):85 Pneumocystis jirovecii, III(2):38 Pneumonia, III(2):48 Pneumothorax - pleural cavity, I(2):17 - tension, II(1):40-43 differential diagnosis, II(1):42 gross and microscopic features, II(1):43 Portal hypertensive gastropathy, II(1):45, 46 Postmortem blood clot, pulmonary thromboembolism vs., II(1):3 Postmortem changes, I(2):12-15 Postmortem interval, definition, I(2):12 Postmortem interventions, external evidence, I(2):9 Postmortem physical exam, I(2):12-13 Postmortem radiography, I(2):94-99 Postpartum hemorrhage, II(1):69 Postpartum pituitary infarction, II(1):85 Postsurgical bleeding, pulmonary hemorrhage vs., II(1):38 PPE. See Personal protective equipment (PPE). Preeclampsia, II(1):69 Pregnancy - complications, II(1):68-73 diagnostic checklist, II(1):70 gross and microscopic features, II(1):71-73 radiologic features, II(1):73 - related hepatic hemorrhage, II(1):56 Pregnancy-associated hematologic disorders, II(1):70 Preliminary anatomic diagnosis (PAD), I(3):108 Prepartum hemorrhage, II(1):69 Primary cardiomyopathy, II(1):9 Primary disease, recurrence of, kidney transplant, III(1):12 Primary graft dysfunction (PGD), lung transplant, III(1):8 Prion disease, suspected, I(2):62 Prostate, examination, I(2):50 Proteins, postmortem changes, I(2):82 Provisional autopsy report, I(3):107 Pseudoaneurysm, thoracic aortic aneurysm repair vs., II(2):134 Pseudomembranous colitis, Clostridium difficile enterocolitis vs., III(2):57 Pseudomembranous enterocolitis, III(2):56-59 Pseudomyxoma peritonei, peritoneal cavity, I(2):18 Pseudoxanthoma elasticum, I(2):71 PTE. See Pulmonary thromboembolism (PTE). PUD. See Peptic ulcer disease (PUD). Puerperal sepsis, II(1):69 Pulmonary arterial bleeding, pulmonary hemorrhage vs., II(1):38 Pulmonary arterial circulation, I(2):24 Pulmonary arteries, I(2):26

INDEX Pulmonary edema, I(2):26, II(1):32-35 - diagnostic checklist, II(1):34 - differential diagnosis, II(1):34 Pulmonary hemorrhage, II(1):36-39 - diagnostic checklist, II(1):38 - differential diagnosis, II(1):38 Pulmonary thromboembolism (PTE), II(1):2-3 - differential diagnosis, II(1):3 Pulmonary vasculature, I(2):26 Pulsatile flow pump VADs, II(2):130 Purge fluid, postmortem, I(2):13 Purkinje cell, II(1):18 Pyelonephritis, III(2):67 - urosepsis, III(2):64 Pyoderma gangrenosum, I(2):71

Q Quilty effect, III(1):4

Radiation injury, neoplasia-associated death, III(3):68 Radiation risk reduction, I(1):7 Radiography, of devices, I(2):79 Rash, I(2):71 Reactive mesothelium, body cavity, I(2):18 Rectum, examination, I(2):36-37 Recurrent hematolymphoid disease, III(1):32 Red marrow, I(2):28 Renal cysts, I(2):50 Renal disease, paraprotein-related, I(2):30 Renal failure - acute, II(1):74-83 differential diagnosis, II(1):77 gross and microscopic features, II(1):79, 83 variant microscopic features, II(1):78, 80-82 - body fluid analysis, I(2):83 - chronic, III(4):92-99 gross features, III(4):96-98 microscopic features, III(4):96-99 Renomedullary interstitial cell tumors, I(2):50 Respiratory arrest, unclear death certification, I(3):103 Respiratory devices, I(2):79 Respiratory failure, ventilator dependent, III(4):82-85 - diagnostic checklist, III(4):84 - gross and microscopic features, III(4):85 Respiratory system, I(2):24-27 - common pathology at autopsy, I(2):26 - postmortem radiography and virtual autopsy, I(2):94-95 - specimen handling, I(2):24-25 Restrictive cardiomyopathy, II(1):10 Reverse electroplating, II(2):119 Rheumatologic diseases, lymph nodes, I(2):29 Rigor, postmortem, I(2):13 Risk, definition, I(1):6 Rokitansky evisceration (en bloc) technique, I(2):48-49 Romanowsky-type stains, I(2):88

Roux-en-Y anastomosis, II(2):142 Roux-en-Y gastric bypass, II(2):146 Rupture, pericardial cavity, I(2):17

Sacral plexus, dissection techniques, I(2):66 Sample collection, guidelines, I(2):84 Sarcoidosis, I(2):29, II(1):19 - myocarditis vs., II(1):14 Sarcoma, Kaposi, III(2):38, 40 Sawing, II(2):119 Scars, examination, I(2):70 Schistosomiasis, I(2):30 Schwannomatosis, I(2):66 Scleroderma, I(2):71 Scrapings, I(2):88, 91 Seizure disorders, II(1):92-95 - diagnostic checklist, II(1):94 - gross and microscopic features, II(1):95 Sepsis, III(2):42-47, 64 - gross and microscopic features, III(2):45-47 - liver, I(2):44 - radiographic features, III(2):45 Serous effusions - pericardial cavity, I(2):17 - pleural cavity, I(2):17 Sezary syndrome, I(2):29, 31 Sharp force risk reduction, I(1):6 Sheehan syndrome, II(1):85 Shock, III(2):42-47 - gross and microscopic features, III(2):45-47 - radiographic features, III(2):45 SIADH (syndrome of inappropriate antidiuretic hormone) production, III(3):75 Sickle cell anemia, I(2):31 Simple pneumothorax, tension pneumothorax vs., II(1):42 Sinoatrial (SA) node, II(1):18, 19 Skeletal system, postmortem radiography and virtual autopsy, I(2):95 Skin laxity, I(2):71 Small bowel, I(2):40 Small intestine, examination, I(2):36 Spinal cord, I(2):61 Spleen, I(2):28 Splenic infarction, I(2):30 Splenomegaly, I(2):30 Squamous cell carcinoma - esophagus, I(2):35 - oral, I(2):74 Stains, cytologic, I(2):88-89 Staphylococcus aureus, blood-borne infections, III(2):64 Stents, radiographic analysis, I(2):98 Stercoral ulcers, I(2):37 Stevens-Johnson syndrome, I(2):71 Stomach, I(2):39 - examination, I(2):35-36 Stress ulcers, I(2):36 Stroke, II(1):104-109 - diagnostic checklist, II(1):106 xi

INDEX - gross and microscopic features, II(1):107-109 Structural deterioration, prosthetic valve failure, II(2):122 Subacute sensory neuronopathy, III(3):75 Subarachnoid hemorrhage (SAH), II(1):100-103 - gross and microscopic features, II(1):102-103 - nontraumatic, II(1):100 - radiologic features, II(1):103 Subdural hemorrhage, II(1):96-99 - acute, II(1):97 - chronic, II(1):97 - diagnostic checklist, II(1):97 - gross and microscopic features, II(1):98-99 - subacute, II(1):97 Sudden cardiac death, I(2):21 Superior vena cava syndrome, II(2):132 Sural nerve, dissection techniques, I(2):66 Surgical devices, I(2):79 Syndrome of Leser-Trélat, III(3):75 Synucleinopathies, III(4):100 Systemic disease, I(2):62 Systemic inflammatory response syndrome (SIRS), III(2):42 Systemic viruses, III(2):60

T. gondii, III(2):40 Tattoos, examination, I(2):70 Tauopathies, III(4):100 Telangiectasia, II(2):158 Tension pneumothorax, II(1):40-43 - differential diagnosis, II(1):42 - gross and microscopic features, II(1):43 Testes, examination, I(2):50 Tetrazolium chloride, acute myocardial infarction, I(2):21 Therapeutic complications, II(2):110-113 - clinically unsuspected diagnoses, II(2):111 - examples of, II(2):110-111 - Goldman criteria, II(2):110 - gross and microscopic features, II(2):112-113 Therapeutic misadventure, II(2):110-113 Thoracic aortic aneurysm repair, II(2):132-137 - differential diagnosis, II(2):134 Thrombi, II(2):124 Thrombocytopenia, I(2):30 Thromboembolism, pulmonary, II(1):2-3 - differential diagnosis, II(1):3 Thromboembolus, II(1):3 Thrombophilia, III(3):68-69 Thrombosis, prosthetic valve failure, II(2):122 Thrombotic microangiopathy (TMA), III(3):69 Thrombus, medical devices, I(2):79 Thymic hyperplasia, I(2):30 Thymoma, I(2):30, 31 Thymus, I(2):28 Thyroid gland - common autopsy findings, I(2):55 - dissection techniques, I(2):54 - gross evaluation/sectioning, I(2):55 - histology, I(2):55 Tissue, procurement, I(2):9 xii

Tissue biopsy, culture, I(2):85 Tissue retention, consent process and legal considerations, I(3):100 Tissue swabs, culture, I(2):85 Tongue laceration, I(2):75 Tonsillitis, I(2):75 Tooth decay, I(2):74 Total inflammation (ti), Banff scoring categories, kidney transplant, III(1):16 Touch preparation, I(2):88, 91 TRALI. See Transfusion-related acute lung injury (TRALI). Transcatheter devices, gross findings, II(2):127 Transfusion-associated circulatory overload, II(2):111 Transfusion-related acute lung injury (TRALI), II(2):111 Transplant glomerulopathy (cg), Banff scoring categories, kidney transplant, III(1):15 Transudates, body cavities, I(2):16 Trauma - central nervous system, I(2):60 - examination, integumentary system, I(2):70 Traumatic injury, pulmonary hemorrhage vs., II(1):38 Trophozoites, intraerythrocytic ring, I(2):31 Trousseau syndrome, III(3):76 Tuberculosis, adrenal insufficiency, II(1):85 Tuberculous pleuritis, body cavity, I(2):18 Tubular atrophy (ct), Banff scoring categories, kidney transplant, III(1):15 Tubular/interstitial diseases, III(4):92 Tubulitis (t), Banff scoring categories, kidney transplant, III(1):15 Tumor lysis syndrome, III(3):68 Tumor-related osteomalacia, III(3):75 Tumors, II(1):45, 46, 56 - See also specific tumors. - central nervous system, II(2):150-155 familial, II(2):150 gross features, II(2):152-153 metastatic, II(2):150 microscopic features, II(2):153-155 post radiation, II(2):150 sporadic, II(2):150 - cytology, I(2):89 - gallbladder, I(2):44 - gynecologic tract, I(2):50 - kidney, I(2):50 - liver, I(2):44 - malignant, exocrine pancreas, I(2):44 - prostate, I(2):50 Turner syndrome, II(1):25

Ulcer, aphthous, I(2):75 Ulcerative colitis, I(2):36, 37 United States of America, autopsy, I(1):3 Upper gastrointestinal (GI) tract, I(2):34 Upper GI bleed, II(1):44-47 Ureters - dissection, I(2):49 - examination, I(2):50

INDEX Urethra, examination, I(2):50 Urinary tract, I(2):48 - gross pathology, I(2):52 Urine - collection of, I(2):83 - components, postmortem changes, I(2):82-83 - culture, I(2):85-86 Urosepsis, III(2):64-67 - gross features, III(2):66 - histologic features, III(2):66-67 - microbiologic features, III(2):67

Valve replacement (including transcatheter), II(2):122-127 - complications, II(2):123 - gross findings, II(2):125 - hemodynamic categories of failure, II(2):122 - infection, gross and microscopic features, II(2):126 - transcatheter devices, gross findings, II(2):127 - types of prosthetic valves, II(2):122 Varicella zoster virus (VZV), III(2):38 Vascular diseases, III(4):92 Vascular ectasias, I(2):75 Vascular inflammation (v), Banff scoring categories, kidney transplant, III(1):15 Vasculitis, II(1):104 Venipuncture, femoral, I(2):85 Venous congestive myelopathy, II(2):156 Venous malformation, II(2):156 Venous outflow obstruction, III(4):86 Venous system, postmortem radiography and virtual autopsy, I(2):94 Venous thromboembolism (VTE), II(1):2-3, III(3):69 Ventilator dependent respiratory failure, III(4):82-85 - diagnostic checklist, III(4):84 - gross and microscopic features, III(4):85 Ventricular assist devices, II(1):9, II(2):128-131 - applications, II(2):128 - in clinical practice, II(2):128 - gross findings, II(2):131 - research opportunities, II(2):128 - types, II(2):128-129 Ventricular puncture, I(2):85 Vertebral artery, I(2):61 Vesalius, Andreas, I(1):3 Vienna school, I(1):3 Viral culture, techniques, I(2):85-86 Viral hemorrhagic fevers (VHF), III(2):60, 62 Viral hepatitis, III(2):60-63 - microscopic findings, III(2):63 - nonhepatotropic, III(2):62 Virchow, Rudolf, I(1):5 Virchow (piecemeal) evisceration, I(2):48 Virtual autopsy, I(2):94-99 - type of imaging, I(2):99 Viruses, cytology, I(2):89 Visceral pleura, I(2):26 Vitreous components, postmortem changes, I(2):83 Vitreous humor, collection of, I(2):83

Vitreous humor electrolyte, abnormalities, patterns of, I(2):83 Volvulus, gastrointestinal system, I(2):36

Whipple procedure, II(2):138 Wilson disease, III(4):86 Wischnewski ulcers, I(2):36 Worm, peripheral blood, I(2):31

X Y Z

Xerostomia, I(2):75

Yellow marrow, I(2):28

Zenker diverticulum, I(2):35 Zollinger-Ellison syndrome, I(2):36, III(3):75

xiii

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